Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy. METHODS: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA). RESULTS: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009). CONCLUSION: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.

Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy.

BACKGROUND: Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma. METHODS: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups. RESULTS: Neither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group. CONCLUSIONS: Expression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid.

Sharpin is a key regulator of skeletal homeostasis in a TNF-dependent manner.

OBJECTIVES: SHARPIN is a subunit of LUBAC and regulates activation of NF-κB, a pivotal transcription factor in skeletal homeostasis. Mutated SHARPIN gene (cpdm) mice develop chronic proliferative dermatitis and systemic inflammation. Cpdm mice have an osteopaenic phenotype characterised by decreased cortical and trabecular bone volume, but whether this is a consequence of the hyper-inflammatory phenotype is unknown. The inflammatory phenotype of cpdm mice is prevented by Tnf deficiency so we examined cpdm.Tnf (-/-) mice to examine the role of SHARPIN in skeletal development. METHODS: This research determined the extent to which SHARPIN and TNF interact within the skeleton through analyses of gene expression, µCT and biomechanical properties of bones of control (CTRL), cpdm, Tnf (-/-) (TNF KO) and cpdm.Tnf (-/-) (cpdm/TNF KO) mice. RESULTS: Gene expression of IL-1ß, TNF and caspase-3 increased in cpdm mice but was comparable to control values in cpdm/TNF KO mice. Decreased cortical and trabecular bone in cpdm mice translated to a loss in bone strength (ultimate stress and peak force). Cpdm/TNF KO mice developed bones similar to, or stronger than, control bones. CONCLUSIONS: Our results suggest that SHARPIN plays a significant role in skeletal homeostasis and that this role is strongly regulated through TNF pathways.

Galnon, a galanin receptor agonist, improves intrinsic cortical bone tissue properties but exacerbates bone loss in an ovariectomised rat model.

OBJECTIVES: Previous studies have shown galanin (GAL) injections onto mouse calvaria increased bone thickness and osteoblast number. This study investigated the effects of the GAL receptor agonist galnon on bone loss using the ovariectomised (OVX) rat model. METHODS: OVX rats were treated with either vehicle or galnon for 6 weeks via mini-osmotic pumps. Plasma osteocalcin concentrations, osseous cell gene expression, morphological and biomechanical properties of the skeleton were compared between the two groups. RESULTS: Treatment with galnon increased RANKL:OPG gene ratio (p<0.001) plus expression of TNF-α (p<0.05) and cathepsin K (p<0.05). µCT analyses revealed galnon-treated OVX animals had reduced trabecular and cortical morphology compared to control animals. Biomechanically, galnon OVX animals required similar peak force to failure to that of control OVX animals although galnon treatment did enhance the mechanical properties of Young's modulus and ultimate tensile stress. CONCLUSIONS: Our research suggests that galnon, a GAL receptor agonist, may enhance osteoclastic bone resorption in OVX rats. Although galnon reduced bone volume, biomechanical testing revealed that bone of galnon-treated animals was mechanically superior per unit area. Taken together, galnon simultaneously improves the intrinsic quality of cortical bone whilst stimulating osteoclastic activity in the OVX rat model.

Recommendations for the practice of travel medicine.

Travel Medicine has emerged as a distinct entity over the last two decades in response to a very substantial increase in international travel and is now forging its own identity, remit and objectives for care of the traveller. Crucial to the formation of any speciality is the definition of recommendations for its practice. This is particularly important and needed for travel medicine as it overlaps with and forms part of day-to-day work in a number of different medical specialities. This document defines a set of recommendations for the practice of travel medicine from the Faculty of Travel Medicine of the Royal College of Physicians and Surgeons of Glasgow. Their objective is to help raise standards of practice and achieve greater uniformity in provision of services, better to protect those who travel. As travel medicine moves towards applying for speciality status, these standards will also contribute to that process.

Systemic inflammatory response is a predictor of outcome in patients undergoing preoperative chemoradiation for locally advanced rectal cancer.

AIM: Current management of locally advanced rectal cancer includes neoadjuvant chemoradiation in selected patients to increase the chance of a tumour-free circumferential resection margin. There is uncertainty over the role of and selection criteria for additional systemic therapy in this group of patients. In this retrospective study we investigate the association between markers of systemic inflammatory response (SIR) and outcome from treatment. METHOD: One hundred and fifteen patients with locally advanced rectal cancer undergoing preoperative chemoradiation had recording of full blood count parameters including neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratios (PLR). Postoperative surgical margins (R status) and pathological stage were documented. Outcome measures were overall survival (OS), time to local recurrence (TTLR) and disease-free survival (DFS). Cox regression analysis was performed to identify predictors of outcome. RESULTS: Only NLR and R status were significant predictors for all outcome measures on univariate and multivariate analysis. Elevated NLR (≥5) was associated with decreased OS, [hazard ratio (HR) and 95% CI, 7.0 (2.6-19.2)], decreased TTLR [HR 3.8 (1.3-11.2)] and shorter DFS [HR 4.1 (1.7-9.8)]. Median survival for patients with an elevated NLR was 18.8 months compared with 54.4 months without an elevated NLR (P<0.001). CONCLUSION: In addition to postoperative R-status, an elevated NLR is also a valuable prognostic marker in patients undergoing chemoradiation for locally advanced rectal carcinoma. It is associated with worse OS, TTLR and DFS. An elevated NLR may be a useful additional tool in guiding the decision-making process for adjuvant or neoadjuvant therapies.

The role of imaging in the pre-operative staging and post-operative follow-up of rectal cancer.

Developments in rectal cancer imaging have revolutionised the management of this condition. It has become increasingly important for oncologists and surgeons to have a working insight into radiological assessment in order to make informed clinical decisions. In this context, we discuss the role that imaging plays in the pre-operative staging, post-operative follow-up and therapy of this disease including some novel advances in the field. Rectal cancer outcomes have improved due to modern surgical techniques, namely total mesorectal excision. Meticulous pre-operative assessment remains key. Conventional TNM staging now appears less crucial compared to assessing tumour distance from the potential plane of surgical resection (particularly the circumferential margin bounded by the mesorectal fascia), and this is reliant on high-quality imaging. Those with margin threatening disease can be offered downstaging chemoradiotherapy to facilitate successful resection. Endorectal ultrasound is useful for T staging and CT for detecting metastases. Malignant lymph node identification remains a problem and the use of size and morphological criteria may lead to misdiagnosis. In the post-operative setting, intensive follow-up is associated with improved outcomes but there are many variations in protocols. Most modalities struggle to differentiate tumour from reactive or fibrotic tissue and functional imaging is being investigated as the solution. PET scanning, particularly PET/CT, has been a major recent development. It has superior utility in detecting recurrent disease, including when conventional imaging is negative, detects occult metastases and may significantly enhance our ability to deliver accurate radiotherapy. Imaging has also opened up avenues for guided therapies aimed at ablating liver metastases. Radiofrequency ablation, in particular, is being used successfully and can improve survival of stage four patients.

Combined modality treatment of early rectal cancer: the UK experience.

With the introduction of colorectal screening in the UK, more patients will probably be diagnosed with early rectal cancer. The UK has an increasingly elderly population and not all patients diagnosed with early rectal cancer will be suitable for radical surgery. Therefore, a national plan is needed to develop the provision of alternative local treatment with equity of access across the country. Here we review the Clatterbridge Centre for Oncology multimodality treatment policy, which has been in clinical practice since 1993 and we discuss its rationale. Clatterbridge is the only centre in the UK offering Papillon-style contact radiotherapy. In total, 220 patients have been treated over 14 years, most of whom were referred from other centres. One hundred and twenty-four patients received Papillon (contact radiotherapy) as part of their multimodality management. The guidelines of the Association of Coloproctology of Great Britain and Ireland recommend local treatment for T1 tumours<3 cm in diameter, but this refers to treatment by surgery alone. There are no published national guidelines for radiotherapy. We plan each treatment in stages and achieve excellent local control (93% at 3 years) with low morbidity. We conclude that radical local treatment for cure can be offered safely to carefully selected elderly patients. Close follow-up is necessary so that effective salvage treatment can be offered. Because of a lack of randomised trial evidence, at present local radiotherapy is not yet accepted as an alternative option to the gold standard surgical treatment. Even with international collaboration, a randomised trial will be difficult to complete as the number of cases requiring local radiotherapy is small due to the highly selective nature of the treatment involved. However, an observational phase II trial is planned. In addition, the Transanal Endoscopic Microsurgery Users Group is also planning a phase II trial using preoperative radiotherapy. These studies will provide evidence to help establish the true role of radiotherapy in early rectal cancer.

Galanin treatment offsets the inhibition of bone formation and downregulates the increase in mouse calvarial expression of TNFalpha and GalR2 mRNA induced by chronic daily injections of an injurious vehicle.

We have previously shown that after bone fracture, galanin (GAL) and GAL receptor expression is increased in osteoblast-like cells of callus; however, the role of elevated GAL/GAL receptors in this instance of bone injury is not known. We hypothesize that in injury, GAL may facilitate bone formation by suppressing the production of cytokines such as TNFalpha and IL-1alpha, thereby affecting bone collagen formation and collagenolysis by key matrix metalloproteinases (MMPs). In studies to explore this hypothesis, we used a mouse calvarial injection model to (1) investigate whether mild injury caused by a daily subcutaneous injection of a glycerol-containing vehicle onto calvaria affected osteoblast/bone formation-associated histomorphometric parameters and gene expression (mRNA encoding GAL, GAL receptors, TNFalpha, IL-1beta, collagen type I, MMP-2 and -13) compared to non-injected, control mice and (2) determine the effect of GAL+vehicle treatment on these entities. Five groups of 4-week-old mice were used: a non-injected control group; a vehicle (50/50 solution of 10 mM PBS+0.025% BSA/5.4 M glycerol)-treated group; and 3 GAL-treated groups (0.2, 2 and 20 ng doses). Solutions were injected subcutaneously onto calvaria in a 10 mul volume, every day for 2 weeks. Vehicle injection reduced calvarial periosteal osteoblast cell height (P<0.001), osteoblast number (P<0.001) and osteoid thickness (P<0.01), relative to values in non-injected animals at 2 weeks. Vehicle injection also inhibited BFR in this periosteal bone relative to values in non-injected animals at both 1 and 2 weeks (P<0.05 and P<0.001, respectively). Increasing concentrations of GAL reversed the above-listed inhibitory effects caused by vehicle. This reversal was demonstrated by a dose-dependent effect of GAL on osteoblast cell height (Pearson's r=0.330; P<0.05), osteoblast number (Pearson's r=0.715; P=0.000), osteoid thickness (Pearson's r=0.516; P=0.000) and BFR (Pearson's r=0.525; P<0.05) after 2 weeks of GAL+vehicle treatment; with the 20 ng/day GAL+vehicle injection schedule returning these measured parameters toward non-injected control values. All GAL+vehicle treatments had no effect on calvarial expression of GAL, GALR1, GALR3, collagen type 1 and MMP-2 mRNAs compared to levels in vehicle-injected controls. GAL treatment did, however, produce dose-dependent effects on calvarial expression of GALR2 (Pearson's r=0.763; P=0.000), MMP-13 (Pearson's r=0.806; P=0.000), IL-1beta (Pearson's r=0.807; P=0.000) and TNFalpha (Pearson's r=0.542; P=0.000) mRNAs with 20 ng/day of GAL+vehicle producing the strongest reversal of vehicle-associated changes. Thus, the 20 ng/day GAL+vehicle regimen offset the inhibition of osteoblastic activity, and therefore bone formation caused by daily glycerol-containing vehicle injection. This effect on bone formation may be due in part to the peptide suppressing the formation and associated activity of TNFalpha, IL-1beta and MMP-13, as TNFalpha and IL-1beta are known inhibitors of bone formation and MMP-13 is involved in collagenolysis. Furthermore, these effects may be due to the action of GAL via GALR2, as it was the only GAL receptor affected by this GAL treatment regimen. These results indicate that GAL can facilitate bone formation associated with injury and reveal potential efficacy for GAL in treating osseous conditions where bone formation may be inhibited due to excess TNFalpha and IL-1beta production.

Evaluation of an inflammation-based prognostic score in patients with inoperable gastro-oesophageal cancer.

There is increasing evidence that the presence of an ongoing systemic inflammatory response is associated with poor outcome in patients with advanced cancer. The aim of the present study was to examine whether an inflammation-based prognostic score (Glasgow Prognostic score, GPS) was associated with survival, in patients with inoperable gastro-oesophageal cancer. Patients diagnosed with inoperable gastro-oesophageal carcinoma and who had measurement of albumin and C-reactive protein concentrations, at the time of diagnosis, were studied (n=258). Clinical information was obtained from a gastro-oesophageal cancer database and analysis of the case notes. Patients with both an elevated C-reactive protein (>10 mg l(-1)) and hypoalbuminaemia (<35 g l(-1)) were allocated a GPS score of 2. Patients in whom only one of these biochemical abnormalities was present were allocated a GPS score of 1, and patients with a normal C-reactive protein and albumin were allocated a score of 0. On multivariate survival analysis, age (hazard ratio (HR) 1.22, 95% CI 1.02-1.46, P<0.05), stage (HR 1.55, 95% CI 1.30-1.83, P<0.001), the GPS (HR 1.51, 95% CI 1.22-1.86, P<0.001) and treatment (HR 2.53, 95% CI 1.80-3.56, P<0.001) were significant independent predictors of cancer survival. A 12-month cancer-specific survival in patients with stage I/II disease receiving active treatment was 67 and 60% for a GPS of 0 and 1, respectively. For stage III/IV disease, 12 months cancer-specific survival was 57, 25 and 12% for a GPS of 0, 1 and 2, respectively. In the present study, the GPS predicted cancer-specific survival, independent of stage and treatment received, in patients with inoperable gastro-oesophageal cancer. Moreover, the GPS may be used in combination with conventional staging techniques to improve the prediction of survival in patients with inoperable gastro-oesophageal cancer.

A phase I dose escalation study of continuous oral capecitabine in combination with oxaliplatin and pelvic radiation (XELOX-RT) in patients with locally advanced rectal cancer.

PURPOSE: To determine the maximum tolerated dose (MTD) of continuous oral capecitabine plus oxaliplatin and pre-operative pelvic radiotherapy (XELOX-RT). PATIENTS AND METHODS: Patients with clinically unresectable rectal cancer or for whom resection with histologically clear (R0) surgical margins was unlikely received continuous capecitabine (500-825 mg/m2 twice daily, 7 days/week), oxaliplatin 2-h intravenous infusion (130 mg/m2 days 1 and 29) and pelvic radiotherapy (Monday-Friday for 5 weeks, total dose 45 Gy in 25 daily 1.8 Gy fractions). The MTD was the capecitabine dose causing dose-limiting toxicities (DLTs; treatment-related grade 3/4 toxicities) in one-third or more of patients treated per dose level. RESULTS: Eighteen patients received three dose levels. The MTD was capecitabine 825 mg/m2 twice daily: DLTs occurred in two of six patients (grade 3 diarrhoea, rectal pain with local skin reaction). No DLTs occurred in six patients receiving capecitabine 650 mg/m2 twice daily. Grade 3/4 toxicity was rare, with minimal myelosuppression. Although predominantly a dose-finding study, XELOX-RT showed promising activity. Fourteen patients had histologically confirmed R0 resections and five had a pathological complete response. CONCLUSIONS: The recommended dose for further study is capecitabine 650 mg/m2 twice daily with oxaliplatin and radiotherapy. XELOX-RT showed promising antitumour activity. Further evaluation is underway.

A phase I and pharmacokinetic study of capecitabine in combination with epirubicin and cisplatin in patients with inoperable oesophago-gastric adenocarcinoma.

BACKGROUND: The purpose of this study was to evaluate the dose-limiting toxicity (DLT) and maximum tolerated dose of capecitabine when used in combination with epirubicin and cisplatin (ECC) in patients with oesophageal or gastric adenocarcinoma. Response rate, progression-free survival (PFS) and overall survival were also determined, and the effect of previous oesophago-gastric surgery or concurrent oesophago-gastric cancer on the absorption and metabolism of capecitabine was evaluated. PATIENTS AND METHODS: Patients with inoperable oesophago-gastric adenocarcinoma received up to six cycles of epirubicin (50 mg/m(2) i.v., 3-weekly), cisplatin (60 mg/m(2) i.v., 3-weekly) and capecitabine, the latter administered orally in an intermittent schedule (14 days treatment; 7-day rest period) at 3-weekly intervals. Patients were recruited into one of four escalating dose cohorts (500, 825, 1000 and 1250 mg/m(2) bd). Dose escalation occurred after six patients had completed at least one cycle of chemotherapy at the previous dose level, with DLT assessed on the toxicity of the first cycle only. Blood sampling for pharmacokinetic analyses was performed over the first 10 h of day 1 of cycle 1. RESULTS: Thirty-two patients, median age 63 years (range 32-76 years), ECOG performance status < or =2 with locally advanced (10) or metastatic (22) disease were recruited and were evaluable for toxicity. Two of five patients experienced DLT at 1250 mg/m(2) bd with grade II stomatitis (one patient) and grade III diarrhoea with febrile neutropenia (one patient). Cumulative toxicity for all cycles (n = 140) (worst grade per patient) includes grade IV oesophagitis (one patient), grade III diarrhoea (five), grade IV neutropenia with infection (seven), grade II stomatitis (four) and grade IV thrombocytopenia (one). Of 29 patients with evaluable disease, there was one complete response and six partial responses [24% response rate [95% confidence interval (CI) 10% to 44%]], a median PFS of 22 weeks (95% CI 17-27 weeks) and median overall survival of 34 weeks (95% CI 19-49 weeks). Capecitabine was rapidly absorbed after oral administration, with a t(max) of 1-2 h for capecitabine, DFCR (5'-deoxy-5-fluorocytidine) and DFUR (5'-deoxy-5-fluorouridine). The C(max) and AUC(0-)( infinity ) for capecitabine, DFCR and DFUR were similar to those observed in previous monotherapy studies of capecitabine taken after food. CONCLUSION: A dose of 1000 mg/m(2) bd of capecitabine is recommended for use on an intermittent schedule in combination with these doses and schedule of epirubicin and cisplatin. This regimen is tolerable and active in oesophago-gastric adenocarcinoma. A randomised phase III comparison with ECF is justified.

Cryptosporidium parvum-specific antibody responses among children residing in Milwaukee during the 1993 waterborne outbreak.

A major gastroenteritis outbreak among >400,000 residents of Milwaukee, Wisconsin, in April 1993 was attributed to Cryptosporidium parvum oocysts in drinking water. Plasma specimens obtained from children (6 months to 12 years old) for routine blood lead level surveillance March-May 1993 were assayed by ELISA for levels of IgG antibody against the immunodominant Triton-17 and 27-kDa C. parvum antigens. Over a 5-week period, the seroprevalence for antibodies to the 2 antigens increased from 15% to 82% and from 17% to 87%, respectively, in samples from children living in southern ZIP code areas (n=218), whereas smaller increases (20% to 43% and 22% to 46%, respectively) were noted among samples from children living in northern ZIP code areas (n=335; P<.0001). The results demonstrate that C. parvum infection was much more widespread than previously appreciated and confirm that infection was associated with residence in the area served by the southern water treatment plant.

Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C.

PURPOSE: N-Benzoyl staurosporine (PKC412) is a protein kinase C inhibitor with antitumor activity in laboratory models. We determined the toxicity of oral PKC412 administered daily for repeat cycles of 28 days. PATIENTS AND METHODS: Thirty-two patients with advanced solid cancers were treated at seven dose levels (12.5 to 300 mg daily) for a total of 68 cycles. RESULTS: The most frequent treatment-related toxicities were nausea, vomiting, fatigue, and diarrhea. At the two top dose levels (225 and 300 mg/d), 15 of 16 patients experienced nausea/vomiting (common toxicity criteria [CTC], version 1), grade 2 in nine of 16 and grade 3 in three of 16 patients; and six of 16 patients developed CTC grade 2 diarrhea. After 1 month of treatment, there were significant reductions in circulating lymphocyte (P <.02) and monocyte (P <.01) counts in patients receiving doses > or = 100 mg/d. Nevertheless, only two patients developed myelosuppression (both grade 2). Of two patients with progressive cholangiocarcinoma, one attained stable disease lasting 4.5 months and one a partial response lasting 4 months. There was a linear relationship between PKC412 dose and area under the curve (0-24 hours) and maximum plasma concentration with marked interpatient variability. The estimated median elimination half-life was 1.6 days (range, 0.9 to 4.0 days), and a metabolite with a median half-life of 36 days was detected. Steady-state PKC412 plasma levels at the top three dose cohorts (150 to 300 mg) were five to 10 times the cellular 50% inhibitory concentration for PKC412 of 0.2 to 0.7 micromol/L. CONCLUSION: PKC412 can be safely administered by chronic oral therapy, and 150 mg/d is suitable for phase II studies. The pharmacokinetics and lack of conventional toxicity indicate that pharmacodynamic measures may be additionally needed to optimize the drug dose and schedule.

A phase II study of epirubicin, cisplatin and raltitrexed combination chemotherapy (ECT) in patients with advanced oesophageal and gastric adenocarcinoma.

BACKGROUND: The aim of this study was to evaluate the efficacy of the combination of epirubicin, cisplatin and ralitrexed (Tomudex). ECT, in patients with advanced oesophageal or gastric adenocarcinoma. Efficacy was assessed primarily as response rate and secondarily in terms of toxicity, time to progression and survival. PATIENTS AND METHODS: Twenty-one patients with histologically and/or cytologically proven unresectable (7) or metastatic (14) gastro-oesophageal adenocarcinoma, who had bi-dimensionally measurable disease, with ECOG performance status < or = 2. with adequate haematological, hepatic and renal function received first-line chemotherapy with epirubicin (50 mg/m2). cisplatin (60 mg/m2) and Tomudex (2.5 mg/m2), ECT, at three-weekly intervals. Treatment consisted of three cycles of chemotherapy, with a further three cycles if there was disease response or stabilisation. RESULTS: ECT is an active regimen in the treatment of advanced gastro-oesophageal adenocarcinoma with an overall intention-to-treat response rate of 29% (95% confidence intervals (CI): 11%-52%). In addition, 4 (19%) patients had stable disease. Median time to progression was 19 weeks (95% CI: 7-31 weeks). Median overall survival was 18 weeks (95% CI: 11-24 weeks). Seventeen patients failed to complete the six cycles of treatment due to disease progression (5). toxicity (3), non-toxic death (1 pulmonary embolism, 1 cardiac), severe allergy to epirubicin (1), patient decision (1) and five patients after the study was discontinued early due to toxicity. There were three toxic deaths: two due to sepsis complicating neutropaenia and one due to cardiorespiratory failure following drug induced enteritis. Nine patients experienced grade 3 or 4 neutropaenia, two patients experienced grade 3 or 4 nausea and vomiting and one patient had grade 4 diarrhoea. CONCLUSIONS: The combination of epirubicin, cisplatin and tomudex is active against advanced gastro-oesophageal adenocarcinoma but the toxicity suggests that further evaluation in a randomised comparison to ECF is not appropriate.

Mortality and prehospital thrombolysis for acute myocardial infarction: A meta-analysis.

CONTEXT: Early administration of thrombolysis for acute myocardial infarction (AMI) may improve survival if safely and appropriately delivered. No systematic reviews that have comprehensively examined this topic exist in the literature. OBJECTIVE: To perform a meta-analysis of randomized controlled trials of prehospital vs in-hospital thrombolysis for AMI measuring in-hospital mortality. DATA SOURCES: The Cochrane search strategy was used to search MEDLINE, EMBASE, and the Science Citation Index (1982-1999); Dissertation Abstracts (1987-1999); and Current Contents (1994-1999) for the terms thrombolysis, thrombolysis therapy, prehospital, and acute myocardial infarction. In addition, text and journal article bibliographies were hand searched, the National Institutes of Health Web site was reviewed, and primary authors and thrombolytic drug manufacturers were contacted for unpublished studies. STUDY SELECTION: Randomized controlled trials of prehospital vs in-hospital thrombolysis for AMI measuring all-cause hospital mortality were included. Two authors independently reviewed 175 citations by title, abstract, or complete article. After exclusion of 30 duplicate citations, 145 studies remained, of which 6 studies and 3 follow-up studies met the inclusion criteria. DATA EXTRACTION: Independent data abstraction by 2 reviewers blinded to the journal, title, and author was confirmed by consensus. Trial quality was independently assessed by 2 other coauthors, blinded to the author, title, journal, introduction, and discussion. DATA SYNTHESIS: The results of the 6 randomized trials (n=6434) were pooled and indicated significantly decreased all-cause hospital mortality among patients treated with prehospital thrombolysis compared with in-hospital thrombolysis (odds ratio, 0.83; 95% confidence interval, 0.70-0.98). Results were similar regardless of trial quality or training and experience of the provider. Estimated (SE) time to thrombolysis was 104 (7) minutes for the prehospital group and 162 (16) minutes for the in-hospital thrombolysis group (P=.007). CONCLUSIONS: Our meta-analysis suggests that prehospital thrombolysis for AMI significantly decreases the time to thrombolysis and all-cause hospital mortality. JAMA. 2000;283:2686-2692.

Non-Hodgkin's lymphoma presenting with spinal cord compression; a clinicopathological review of 25 cases.

The aim of this study was to retrospectively examine 25 patients with newly diagnosed non-Hodgkin's lymphoma (NHL) presenting with spinal cord or cauda equina compression as the first symptom that were referred to our department between 1985 and 1996. At presentation 17 patients were non-ambulatory; dual sphincter impairment was found in 9 patients with a further 8 patients having bladder dysfunction only. All patients had a tissue diagnosis. Five low-grade and 20 intermediate or high-grade tumours were identified. In this latter group 4 patients were treated palliatively and the remaining 16 patients received combination chemotherapy and/or radical radiation therapy. The overall survival at 5 years is 59%. The majority of patients became ambulatory, even if paretic at presentation. This is in marked contrast to reports of patients presenting in this fashion due to metastatic carcinoma. We urge this diagnosis be considered in all patients presenting with spinal cord compression attributed to malignancy.

Eighteen-month follow-up of infants fed evaporated milk formula.

In parts of Canada including Newfoundland and Labrador and among Aboriginal peoples, infants still consume evaporated milk (EM) formulas for cultural and economic reasons. At 3 and 6 months, full-term infants fed EM (n = 30) received low intakes of iron, thiamine, selenium and had higher weight velocity than breastfed (BF, n = 29) infants. EM infants had greater anemia, lowered transketolase activity (thiamine) and lowered glutathione peroxidase (selenium) activity (p < 0.05). To determine the later effect of early feeding deficit on nutritional status, we examined these same infants at 18 months of age. At that time, there were no differences in dietary intakes of energy, protein, zinc, copper, selenium and iron, nor in plasma levels of zinc, copper, vitamin C, nor in red blood cell activity levels of glutathione reductase (riboflavin), transketolase, glutathione peroxidase, nor in superoxide dismutase. However, EM infants weighed more and were more likely to visit a physician, have anemia, and have iron depletion than were BF infants. We conclude that infants consuming evaporated milk formulas should receive iron supplements throughout infancy.

Induction of p53-dependent and p53-independent cellular responses by topoisomerase 1 inhibitors.

We have previously shown that loss of p53 function in A2780 human ovarian adenocarcinoma cells confers increased clonogenic resistance to several DNA-damaging agents, but not to taxol or camptothecin. We have now extended these studies, comparing wild-type p53-expressing A2780 cells with isogenic derivatives transfected with a dominant negative mutant (143; val to ala) p53. We show that, as well as retaining equivalent clonogenic sensitivity to camptothecin, mutant p53 transfectants of A2780 cells do not acquire significantly increased resistance to the camptothecin analogues topotecan and SN-38, the active metabolite of CPT-11. Compared with vector-alone transfectants they are, however, relatively (2.2-fold) resistant to GI 147211, a further camptothecin analogue undergoing clinical trial. Treatment of A2780 with camptothecin and each analogue produces an increase, maximal at 24-48 h after drug exposure, of cells in the G2/M phase of the cell cycle and a decrease in both G1 and S-phase cells. The G2 arrest is independent of p53 function for camptothecin and the three analogues. All four compounds can induce apoptosis in A2780, which is reduced in mutant p53 transfectants, as measured using the terminal DNA transferase-mediated b-d UTP nick end labelling (TUNEL) assay. Thus, although p53-dependent apoptosis is induced by camptothecin, topotecan and SN-38 in this human ovarian carcinoma cell line, these drugs induce p53-independent death, as measured by clonogenic assay.

A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate.

LY231514 is a novel antifolate that principally inhibits thymidylate synthase, but with additional folate-dependent enzyme targets. A Phase I study of single-agent LY231514 administered as a daily i.v. infusion over 10 minutes for 5 days, repeated every 3 weeks, was conducted to evaluate the maximum tolerated dose, pharmacokinetic profile, and antitumor activity of the drug using this schedule. Thirty-eight patients with advanced malignancies that were refractory or not amenable to standard therapy were treated with a total of 116 courses of LY231514, escalating treatment doses through 10 dose levels, from 0.2-5.2 mg/m2/day. No objective clinical responses were observed, although minor antitumor activity not fulfilling the response criteria was seen in three patients. A maximum tolerated dose of 4.0 mg/m2/day was determined, with neutropenia as the predominant dose-limiting toxicity. Reversible disturbances of liver biochemistry, fulfilling the protocol definitions of dose-limiting toxicity, were also observed. Other toxicities included diarrhea, mucositis, skin rash, and fatigue. Pharmacokinetic studies were performed at all treatment levels. Analysis showed a linear relation between administered dose and both maximum plasma concentration (Cmax) and area under the plasma concentration/time curve. The drug was cleared with a day 1 total body clearance of 108.9 +/- 38.8 ml/min/m2, with plasma concentrations declining with a mean harmonic terminal half-life of 1.4 +/- 0.98 h. When given by this schedule, LY231514 is tolerable, and Phase II studies are in progress.