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BACKGROUND: Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer.METHODS: This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m 2 twice daily on days 1–14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13.FINDINGS: Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37–60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6–59·1) in the capecitabine group compared with 36·4 months (29·7–44·5) in the observation group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63–1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55–0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30–44) in the observation group (adjusted HR 0·75, 95% CI 0·58–0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6–35·9) in the capecitabine group and 17·5 months (12·0–23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8–46·3) in the capecitabine group and 17·4 months (12·0–23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (INTERPRETATION: Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting.FUNDING: Cancer Research UK and Roche.

OBJECTIVE To assess the prognostic significance of stress echocardiography in women with a high probability of coronary artery disease (CAD). SETTING Secondary and tertiary cardiology unit at a university teaching hospital. PARTICIPANTS A total of 135 women (mean (SD) age 63 (9) years) with pre-test probability of CAD ⩾80% were selected from a database of patients investigated by treadmill or dobutamine stress echocardiography between 1995 and 1998. MAIN OUTCOME MEASURES Patients were followed up for occurrence of subsequent cardiac events (cardiac death, myocardial infarction, admission with unstable angina, and revascularisation) using a structured telephone interview and case note review. RESULTS Each patient had between two and seven (mean 3.5) CAD risk factors and pre-test probability of CAD ⩾80%. Ninety three patients (68.9%) had negative stress echocardiography. Mean (SD) follow up was 20.1 (8.5) months. There were six events in the positive stress echocardiography group (two cardiac deaths, one unstable angina, three revascularisations), and one event in the negative stress echocardiography group. Cox regression analysis showed positive stress echocardiography (p=0.02) and age (p=0.03) to be the only univariate predictors and positive stress echocardiography to be the only independent predictor of future cardiac events (relative risk 8.9, confidence interval 1.0 to 76.5, p=0.04). Cumulative event free survival to 38 months was 98% in the negative stress echocardiography and 50.7% in the positive stress echocardiography groups. CONCLUSION In women with high pre-test likelihood of CAD: (1) negative stress echocardiography identifies a subgroup with low risk of cardiac events who do not require further invasive investigation and (2) positive stress echocardiography identifies a subgroup with increased risk of subsequent cardiac events.

We use polyharmonic Radial Basis Functions (RBFs) to reconstruct smooth, manifold surfaces from point-cloud data and to repair incomplete meshes. An object's surface is defined implicitly as the zero set of an RBF fitted to the given surface data. Fast methods for fitting and evaluating RBFs allow us to model large data sets, consisting of millions of surface points, by a single RBF — previously an impossible task. A greedy algorithm in the fitting process reduces the number of RBF centers required to represent a surface and results in significant compression and further computational advantages. The energy-minimisation characterisation of polyharmonic splines result in a “smoothest” interpolant. This scale-independent characterisation is well-suited to reconstructing surfaces from non-uniformly sampled data. Holes are smoothly filled and surfaces smoothly extrapolated. We use a non-interpolating approximation when the data is noisy. The functional representation is in effect a solid model, which means that gradients and surface normals can be determined analytically. This helps generate uniform meshes and we show that the RBF representation has advantages for mesh simplification and remeshing applications. Results are presented for real-world rangefinder data.

ONO-4007 is a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide, which exhibits antitumor activity by the induction of intratumoral tumor necrosis factor alpha, the potentiation of tumor-infiltrating macrophages, and the inhibition of angiogenesis. Interleukin (IL)-1 alpha, IL-6, and IL-12 induction by ONO-4007 activates cytotoxic natural killer cells to up-regulate IFN-gamma and nitric oxide synthase activity. ONO-4007 was given to 24 patients (13 males and 11 females; median age, 53 years) as a 30-min i.v. infusion on day 1, followed on day 15 by a first treatment cycle consisting of three weekly infusions at the same dose, followed by a rest period of 1 week. Cohorts of six patients received up to a maximum of four treatment cycles at increasing dose levels (75, 100, and 125 mg). The maximum tolerated dose was 125 mg, with grade 3 National Cancer Institute Common Toxicity Criteria toxicity (rigors with cyanosis) occurring in two of six patients at this dose level. An additional six patients were treated at 100 mg, the dose below the maximum tolerated dose. Other toxicities included grade 2 National Cancer Institute Common Toxicity Criteria myalgia, nausea, and hypotension. The pharmacokinetics of ONO-4007 appeared to be independent of dose and showed linearity with respect to time. ONO-4007 has a low systemic clearance (approximately 1.3 ml/min) and a small volume of distribution (5-8 liters) with a long t1/2 of 74-95 h. The administration of ONO-4007 was shown to result in a significant increase in circulating levels of tumor necrosis factor alpha and IL-6. No objective antitumor responses were observed. Seven patients maintained stable disease for at least two cycles, whereas five patients maintained stable disease for the full four-cycle duration of the study. Additional studies are required to determine the antitumor activity of ONO-4007.

The association of neoplastic disease and thromboembolic disorders was first recognized by Trousseau in 1865. Abnormalities of blood coagulation tests have been reported in the majority of patients with cancer, including ovarian carcinoma. However, Trousseau's syndrome has rarely been reported in women with ovarian carcinoma.A literature search for cases of Trousseau's syndrome in association with ovarian carcinoma was performed using the MEDLINE database. Case notes of patients with ovarian carcinoma treated at St. George's Hospital were reviewed and cases of Trousseau's syndrome identified.We report a series of 4 cases of Trousseau's syndrome in association with ovarian carcinoma occurring over a 3- to 4-year period, and highlight the particular difficulties associated with the management of these thromboembolic effects.Trousseau's syndrome can impair quality of life in patients with advanced ovarian carcinoma and enhanced anticoagulation regimens may be required for effective palliation.

Eosinophilic pustular folliculitis is a rare disorder previously reported predominantly in Japanese people who are otherwise healthy. Recently, the disorder has been noted in patients with acquired immune deficiency syndrome, as has eosinophilic folliculitis, a similar but distinct entity. The authors report a patient with eosinophilic folliculitis who was immunocompromised after high dose chemotherapy and bone marrow autograft for treatment of non-Hodgkin's lymphoma.

Automatic external defibrillators (AEDs) provide a means of reducing the response time in cardiac arrests but policies based on their use must take into account the costs of retraining. These depend on the level of retention of skills over time. This paper describes the retention of skills by student nurses following a training programme on the use of AEDs in cardiac resuscitation. Sixty-three student nurses were studied at intervals of 1 week, 1, 3 and 6 months following training. There was a slight deterioration in skills at 1 week and 1 month but the scores returned to the baseline level at 3 months and remained there. We conclude that there is now a case for a major study of the use of nurse-operated AEDs in the hospital setting.

Aromatase inhibitors are a useful therapeutic option in the management of endocrine-dependent advanced breast cancer. A single-dose administration of exemestane (FCE 24304; 6-methylenandrosta-1,4-diene-3,17-dione), a new irreversible aromatase inhibitor, was investigated in 29 healthy postmenopausal female volunteers. The compound, given at p.o. doses of 0.5, 5, 12.5, 25, 50, 200, 400, and 800 mg (n = 3-4), was found to be a well tolerated, potent, long-lasting, and specific inhibitor of estrogen biosynthesis. The minimal dose which produced the maximum suppression of plasma estrogens was 25 mg, reducing plasma estrone, estradiol, and estrone sulfate to 35, 28, and 39% of basal values, respectively. This maximum suppression, observed at 3 days, persisted for at least 5 days after administration of a single dose. However, there was no interference on cortisol, aldosterone, 17-hydroxyprogesterone, or dehydroepiandrostenedione sulfate plasma levels. Peak plasma exemestane concentrations of 27, 221, 343, and 414 ng/ml were reached within 2 h after administration of 50, 200, 400, and 800 mg, respectively. Plasma concentrations declined rapidly and fell under the detection limit (10 ng/ml) at 4 (50 mg) or 24 h (200 and 400 mg). No clinically significant adverse events which could be attributed to the drug were reported. Apart from transient eosinophilia in 3 patients, all biochemical and hematological laboratory parameters were within 1.25-fold of the normal ranges.

Lactic acidosis B is a rare metabolic complication of malignancy. It usually is associated with advanced and extensive metastatic disease. The authors report a case in which lactic acidosis was the presenting feature of a previously undiagnosed case of metastatic breast cancer in a pregnant woman and that resolved with successful antineoplastic treatment. The authors review the likely cause and management of the condition.

2511 Background: PM02734 is a chemically synthesized depsipeptide with a broad spectrum of activity against solid tumors in vitro (breast, colon, lung, neuroblastoma, prostate, sarcoma and thyroid) and in vivo (breast, prostate, melanoma); as well as an acceptable non-clinical toxicology profile. Methods: Patients (pts) with metastatic or advanced solid tumors were enrolled in a phase I, open-label, dose-escalating study to assess safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting toxicity (DLT) and recommended dose (RD) of PM02734 infused over 24 hours every 21 days (d). The starting dose was 0.48 mg/m2. Cohorts of 1–6 pts were treated at different dose levels. Results: Thirty seven pts were treated in this study. The median age was 55 years (40–75), sex: males/females 20/19. The median PS was 1 (range 0–2). The most frequent cancer types were colon/ gastric/ sarcoma (n=8/5/5). Most patients were heavily pretreated, with a median of prior therapy lines of 4 (1–12). Patients were treated at 8 dose levels (0.48, 0.72, 1.0, 1.6, 2.4, 3.6, 5.4, and 6.8 mg/m2), the MTD was 6.8 mg/m2 and the RD was 5.4 mg/m2 (10 mg flat dose).Common toxicities grade ≤ 2 included asthenia, nausea/emesis, lymphopenia, injection site reactions and asymptomatic elevated transaminases (TAs). DLT were grade 3 asymptomatic, reversible TA elevations at 6.8 mg/m2. Preliminary PK data is characterized by long half life (>100 h), a wide distribution and high inter-patient variability. Clearance was not correlated with dose or body surface area (BSA), therefore, flat dose was implemented and the RD was explored with this schedule. Efficacy data showed one complete response (CR) of +28 months observed in a pt with metastatic large cell esophageal carcinoma, and five more showed stable disease (SD) for more than 3 months in different histologies. Conclusions: PM02734 shows to be safe, well tolerated and with evidence of activity (1 CR and 5 SD > 3 months) in pts with advanced solid tumors. The DLT was grade 3 asymptomatic and reversible TA elevations, and the RD for further phase II studies is 10 mg. [Table: see text]

3550 Background: EGFR and VEGFR are important targets in a number of human cancers with common downstream signalling pathways. Combined blockade of EGFR-VEGFR with E and OSI-930 has shown additional antitumor activity compared to either agent alone with long-term remissions in multiple xenograft models. Methods: Sequential cohorts of pts with advanced refractory solid tumors were treated with OSI-930 BID with addition of E QD from Day 8 and beyond to determine the maximum tolerated dose (MTD) and to evaluate safety, PK and efficacy of the combination. Escalation followed a standard 3+3 design until dose-limiting toxicity (DLT) was observed in ≥ 2/6 pts. PK of OSI-930, E and its metabolite OSI-420 were determined. Levels of soluble VEGFR2 (sVEGFR2) in plasma were also measured. Results: 16 pts have been entered (13M/3F); median age 63 years (range 41–78), PS ≤2 and 38% pts with mCRC. OSI-930/E were administered at 3 levels [mg(pts entered/evaluable)]; 200 BID/100 QD (7/6), 200 BID/150 QD (4/3), and 300 BID/150 QD (5/5). Median duration of therapy was 8 weeks (range 1–22). DLT was seen in 1/6 pts at 200 BID/100 QD (>5 day interruption due to G4 neutropenia); and 1/5 at 300 BID/150 QD (G3 Asthenia/lethargy). Other common related toxicities (% all grades:% g3/4) were: skin-related (rash, HFS etc) (85:23), Asthenia/lethargy/fatigue (69:15), diarrhea (77:8), anorexia (92:0), and transaminitis (31:15). Reduction and/or interruptions of one or both study drugs during or beyond the initial 28 days were required in 8/14 pts. Six of 11 pts evaluable for response achieved SD ≥12 weeks. Median plasma Cmax (and AUCTau) of OSI -930 for Cohort 3 (300 BID/150 QD) were: 0.826 (6.08), 0.947 (5.57), and 1.66 (14.3) μg/mL (μg.hr/mL) on Days 7, 8 and 22, respectively. Exposure of OSI-930 increased approximately 2-fold upon co-administration with E at steady-state. OSI-930 appeared not to alter the PK properties of E or the ratio of OSI-420 to E. Decreases in plasma sVEGFR2 were observed, indicating a PD effect of OSI-930. Conclusions: Additional patients are being added to confirm the MTD of the combination. PK data indicate a drug-drug interaction with doubling of the OSI-930 exposure on co-administration with E. [Table: see text]

2559 Background: OSI-906 is a potent small molecule inhibitor of IGF-1R, a receptor tyrosine kinase activated by insulin like growth factor, which is overexpressed in numerous malignancies and implicated in resistance to chemotherapy. Methods: Patients with advanced cancer entered escalating dose cohorts of OSI-906. Study objectives included assessment of: safety; determination of MTD; pharmacokinetics (PK), pharmacodynamics (PD) including IGF-1R levels in peripheral blood cells; and tumor response (RECIST). Results: To date, 32 pts have been treated (22M/10F, median age 62y) at 10, 20, 40, 75, 150, and 300 mg QD and at 20, 40 mg and 75 mg BID. Median number of weeks on trial was 6 (range 0–44). No DLTs have been observed. Hyperglycemia (5/20 pts) related to OSI-906 was transient and mild (grade 1 only). In addition to hyperglycemia, grade 1–2 nausea and vomiting (5/20 pts) were the most frequent related adverse events (AEs). There was grade 3 elevated lipase in 1 pt. At doses of 10–150 mg, OSI-906 exhibited linear PK, median terminal t1/2 ranged from 2.18–4.30 hr, AUC0-inf from 284–10200 ng.hr/mL, and Cmax 76.6–1440 ng/mL. There was no relationship between glucose or insulin levels and OSI-906 plasma concentrations. Stable disease > 12 weeks was seen in 7/20 pts (range 12–34 weeks), including 1 pt each with thymic (27 w), adrenocortical (28w), and colorectal (34w) cancer. PD data on IGF-1R phosphorylation will be presented. Conclusions: Plasma concentrations of OSI-906 achieved in this trial exceed concentrations required for antitumor efficacy in preclinical models. PD target modulation and preliminary anti-tumor activity have been observed. It is interesting to note that clinically meaningful hyperglycemia has yet to occur. Minimal toxicity was observed and further dose escalation is in progress. [Table: see text]

14533 Background: Cediranib (AZD2171) is an oral, highly potent and selective inhibitor of vascular endothelial growth factor (VEGF) signaling, with activity against VEGFR-1, -2 and -3. The effect ...

3526 Background: E7080 is a potent inhibitor of the split-kinase family of transmembrane growth factor receptors including VEGFRs 1 and 2, and also potently inhibits FGFR-1 and PDGFR-β tyrosine kinase activities. E7080 inhibited VEGF-driven umbilical vein endothelial cell proliferation and tube formation in vitro, and inhibited tumor growth in H460 and Colo205 mouse xenografts models in vivo at doses of 1–100mg/kg. Methods: The primary objective of this study was to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of E7080 in pts with advanced solid tumors refractory to standard therapies. Eligible pts were those with ECOG PS < 2 and adequate haematologic, renal and hepatic function. E7080 was administered orally on a once daily continuous schedule in 4-week cycles. Dose escalation was by an accelerated design (100% dose increases until the 1st pt experienced toxicity ≥ grade 2). Samples for pharmacokinetic (PK) analyses were collected on days 1, 8, 15, 22 and 29. A food effect ...

Preregistration house officers need to be able to manage the first 5–10 minutes of a cardiac arrest. A course has been designed based on the recommendations of the Resuscitation Council UK 1984 and the format of the American Heart Association advanced cardiac life support course. Fifty-nine newly qualified doctors from the same medical school class were studied in two consecutive groups: Group 1 (n = 31) were commencing their first post and Group 2 (n = 28), whose first preregistration post had been at other hospitals without practical resuscitation training, were commencing their second post. They were pretested and taught in three 2-hour sessions. Five months later they were tested to measure retention of knowledge and skills. Before training there was no difference in knowledge between the two groups but Group 1 were more skilled. The knowledge and skills of both groups immediately after training were significantly improved and at 5 months skills were subject to modest decay only. Experience of managing cardiac arrests was not a substitute for formal practical training.

2544 Background: TL310 is a novel, oral taxane with potent pre-clinical activity in taxane-resistant model systems. This is the first study to evaluate the safety, tolerability and pharmacokinetics (PK) of TL310 in pts with advanced refractory solid tumors. Methods: Pts with adequate hematologic, renal, and liver function received TL310 administered orally on days 1, 8 and 15 of a 28-day cycle. Pts were continuously assessed for safety and dose-limiting toxicity (DLT) was based on first cycle toxicity only. A rapid dose escalation schedule was used (1 pt per dose level until ≥ grade 2 toxicity then 3–6 patients per cohort). The maximum tolerated dose (MTD) was defined as the dose level below that at which ≥ 2 of 3–6 pts experienced DLT. PK sampling was performed on days 1, 2, 3–4, 8, 15, 16, 17–18, 22 of cycle one. Serial imaging with CT was performed every 8 weeks to assess response. Results: 18 patients [M=11, F=7], ECOG PS ≤ 2 were treated with doses of 5 (1 pt), 10 (1pt), 20 (1pt), 40(2pts), 80 (5pts), 120 (3pts) and 160 mg/m2 (5pts). 1 pt had grade 2 vomiting at 80mg/m2. This, and subsequent, dose levels were expanded to include 3 pts. 3 pts (2 at 80 and 1 at 160 mg/m2) vomited immediately after drug administration during cycle 1 and were replaced. 1/5 patients experienced a DLT at 160 mg/m2 with G5 neutropenic sepsis, G4 neutropenia and G4 thrombocytopenia. No other grade 3/4 toxicities attributed to study drug have occurred. Of 18 patients assessable for response, 1 had a partial response (gastric cancer) at 80 mg/m2 and 6 had stable disease for > 2 cycles (esophageal 3, melanoma 1, ovary 1, cervix 1). The maximum concentration (Cmax) increased with dose up to 120 mg/m2, but appeared to plateau (86±6 ng/ml) in 4 of 5 patients at 160 mg/m2. TL310 has a half-life of up to 80 hours, but PK were very similar on successive courses of treatment. Conclusions: TL310 can be administered orally up to 160 mg/m2 on day 1, 8, 15 of a 28 day cycle and shows promising activity at doses below the MTD. The MTD has not yet been defined and dose escalation continues. No significant financial relationships to disclose.

14073 Background: E7080 is a potent inhibitor of the split-kinase family of transmembrane growth factor receptors including Flt-1 and KDR. In addition, E7080 also potently inhibits FGFR1 and PDGFRβ tyrosine kinase activities. In an in vitro angiogenic model, E7080 inhibited VEGF-driven umbilical vein endothelial cell (HUVEC) proliferation and tube formation. Using H460 and Colo205 mouse xenograft models, E7080 significantly inhibited tumor growth at doses from 1 to 100 mg/kg. Methods: A Phase I and pharmacologic study was conducted to determine the Maximum Tolerated Dose (MTD) and Dose Limiting Toxicity (DLT) of E7080 in pts with advanced malignancies. Eligible pts with adequate hematologic, renal and hepatic function, and with tumors refractory to standard therapies, were treated with E7080 administered orally on a once daily continuous dose schedule in cycles of 4 weeks. Dose escalation was performed according to an accelerated design of 100% dose increases in subsequent cohorts until the first patient experienced ≥ CTC grade 2 toxicity. Results: As of November 17th, 2006, 37 pts with documented progressive disease (PD) have been treated at the following dose levels: 0.2 mg/d, 0.4 mg/d, 0.8 mg/d, 1.6 mg/d, 3.2 mg/d, 6.4 mg/d, 12.5 mg/d and 16 mg/d. Median number of cycles was 1 (0–11). Median age = 60 years (25–84), 20 pts were male, 17 were female. 37 pts were evaluable for toxicity. 1 patient experienced grade 3 hypertension (DLT) in the 16 mg/d cohort, other related toxicities ≥ grade 2 include hemorrhage and thrombosis (n=1), tachycardia (n=1), febrile neutropenia (n=1), proteinuria (n=1), thrombocytopenia (n=1) and hypertension (n=1). MTD has not been reached and this study is continuing to recruit. 24 pts were evaluable for efficacy, 3 are too early to evaluate. 1 patient had a partial response (high grade sarcoma) after 2 cycles, and 15 pts experienced stable disease from 2+ to 11 months, and 11 pts continue on therapy. Pharmacokinetic (PK) studies: preliminary data suggest that the PK is linear over the range 0.2 mg/d to 12.5 mg/d. Conclusions: E7080 is safe and well tolerated at doses acheived so far and has shown promising first signs of anti-cancer activity associated with potent activity in pre-clinical models. Clinical and PK data from subsequent doses and follow- up will be presented. No significant financial relationships to disclose.

SummaryDaily supplements of dried Leucaena leaf meal (500 g/head) were offered for 3 weeks to steers in metabolism cages. The steers had previously been fed diets of oaten chaff (5 kg/head/day) ormclasses and urea (4·5 kg/head/day) with restricted forage (2 kg/head/day). Excretion rates of the primary degradation product of mimosine, 3-hydroxy-4(1H) pyridone (DHP) by steers fed the two diets were compared. These compounds appeared in urine on the 1st day after Leucaena feeding had commenced and output remained fairly constant after 4 days. Mean weekly urinary outputs (g) of DHP from steers fed the oaten chaff or molasses + urea diet were 13·45 and 7·50 respectively. These levels corresponded to 0·23 and 0·13 of the amounts ingested. When steers were fed the molasses + urea diet, DHP continued to appear in urine up to 5 days after Leucaena had been withdrawn from the diet. On the oaten chaff diet no DHP was detected after 3 days following withdrawal of Leucaena.The effects of casein or formaldehyde-treated casein supplements on the output of urinary DHP by steers fed oaten chaff plus Leucaena was evaluated in a second experiment which ran concurrently. The animals were fed the test diets for 3 weeks before collections were made. Mean DHP outputs (g/day) from animals fed the control diet, control diet plus casein or control diet plus formaldehyde-treated casein were 1·89, 2·21 and 2·44 respectively.These results confirm substantial degradation of DHP and that the extent of degradation can be affected by the dietary regime in which Leucaena is fed.

Twenty five patients who had undergone conventional coronary arteriography and left ventriculography for suspected coronary artery disease had left ventriculography performed by digital subtraction angiography as outpatients; there were no complications requiring admission to hospital. A catheter was introduced percutaneously and positioned in the superior vena cava; 40-50 ml of contrast medium was injected at 16-18 ml/s. Left ventriculograms were recorded in the 30 degrees right anterior oblique projection. Diagnostic images were recorded in each case. Left ventricular wall movement was assessed as normal in nine patients, globally hypokinetic in 10, and aneurysmal in six. In each case there was agreement between the two methods. Ejection fraction varied between 17% and 78%. It is concluded that digital subtraction angiography provides a reliable assessment of overall left ventricular function and distinguishes between those patients with a potentially resectable lesion and those with global impairment of function.

Two cases of histologically proven pulmonary fibrosis resulting from amiodarone therapy but responding to corticosteroids are reported.

Stroke volume was determined from the pulmonary artery pressure record by application of the pulse contour method. Pulmonary artery pressure records were obtained in 17 patients using a high fidelity catheter-tip pressure transducer and simultaneous measurements of cardiac output were obtained from indicator dilution curves. The formula used was SV = KP sa (i plus T s/Td) where Psa is the planimetered area beneath the systolic portion of the pulmonary artery pressure curve. Ts and Td are the durations of systole and diastole, and K is a constant. Stroke volume was altered by isometric handgrip exercise and/or pharmacological agents in 15 patients. Serial measurementswere made in 2 patients in acute pulmonary oedema after myocardial infarction. Comparison of a wide range of values of stroke volume by the pulse contour method with those obtained from dye dilution curves showed a good correlation (r plus 0.97, P smaller than 0.001) regression line y = 1.01 times - 0.47. Measurement of stroke volume from the pulmonary artery pressure contour is a technique of potential value in serial haemodynamic monitoring.

Since 1970, the number of heat flow observations in the Red Sea has increased fivefold. A new heat flow map is presented together with a table of observations. The new data confirm that the whole of the Red Sea is associated with high heat flow. The observations within 5 km distance of the deepest water of the axial trough have a mean of 467 mWm-2 (i.e. about eight times the world mean) and the observations from 50 to 170 km from the axial deep water have a mean of 111 mWm-2 (i.e. about twice the world mean). The heat flow distribution is thus typical of that associated with an active spreading centre. The observations are difficult to assess and interpret in detail because of the complex sedimentary and tectonic environment. The high heat flow extends at least as far as the Red Sea coasts.

Assessment of a patient monitoring system used in a general medical intensive care ward showed that the blood pressure subsystem was unreliable. The method used in this study is discussed in relation to the clinical requirements of patient monitoring apparatus.

We present clinical and electrophysiological data on 9 patients with paroxysmal reciprocating sinus tachycardia (PRST) of whom only 6 described palpitations. Sinus node disease was present in 5 and cardiac ischemia and/or hypertension in another 3; the remaining case had apparently coincidental Wolff-Parkinson-White (WPW) syndrome. PRST could be initiated in all cases, and terminated in the 4 in whom it was sustained, by suitably timed atrial premature beats over a zone that was dependent on the effective atrial extrastimulus coupling interval (A1-A2) in the high right atrium (HRA). The sequence of atrial depolarization during PRST was similar to that of sinus beats although minor changes in both the P wave and the configuration of the HRA electrogram were observed in half the cases. During paroxysms, cycle length variation and sensitivity to alterations in vagal tone were common. In 6, paroxysms could be initiated by moderately rapid atrial pacing. Repetitive attacks were usually initiated by increases in the sinus rate and not be an antecedent premature atrial extrasystole. Verapamil suppressed sinus node reentry in 5 patients while small doses of atropine favored initiation in 3. PRST was seen in association with AV reentry tachycardias in the patient who had the WPW syndrome.

Ten years' experience of cardiac Munchausen's syndrome in the Cardiac Care Unit of an Inner London teaching hospital is reported. Thirty-six admissions in this category were identified and analysed, and 4 typical cases are described. The common presenting complaints, recurring features and the relationship with other forms of Munchausen's syndrome are discussed, as are posible strategies available to deal with this clinical entity.

Platelet function was studied during coronary angiography of patients complaining of chest pain. The following changes occurred 5 min after injecting 100 IU·kg−1 body weight of a conventional high molecular weight heparin: ( a ) a significant fall in platelet count; ( b ) a significant enhancement of platelet aggregation in platelet rich plasma (turbidometric technique) and in whole blood (platelet impedance aggregation technique); and ( c ) significantly enhanced release of platelet thromboxane A2, a vasoconstrictor. These changes tended to reverse towards baseline values 5 min after injecting a contrast medium (Conray 420), which was found to inhibit platelet aggregation. Thus heparinisation with a high molecular weight heparin seems to cause pronounced activation of platelets in patients undergoing coronary angiography, and this may contribute to the pathogenesis of cardiac ischaemia that may occur during this procedure. Since coronary artery bypass surgery in similar patients involves the use of heparin at much higher doses without the concomitant use of an antiaggregatory contrast medium, it is possible that platelet hyperaggregability may contribute to the well documented ischaemic brain injury associated with this form of surgery. Furthermore, the use of high molecular weight heparin after successful coronary angioplasty or thrombosis may influence the incidence of reocclusion. These findings therefore suggest that low molecular weight heparinoids should be evaluated in these situations since these anticoagulants are only weak activators of platelet aggregation.

Nicardipine is a new slow channel calcium blocker. It has been shown to be effective in the treatment of hypertension and angina pectoris. Nine patients with mild to moderate left ventricular failure were given intravenous infusions of nicardipine and the haemodynamic effects measured. In patients receiving 20 mg of nicardipine, mean cardiac index rose to a peak 1.81 X min-1 X m-2 (64%) above the preinfusion level, stroke volume index rose by 12 ml X m-2 (35%) and heart rate rose by 16 beats X min-1 (20%). There was a significant fall in systemic vascular resistance of 50% manifested by a reduction of 22 mm Hg in systolic blood pressure (18%) and 18 mm Hg in diastolic blood pressure (22%). Pulmonary vascular resistance fell by 45%. Mean pulmonary artery pressure and capillary wedge pressure did not change significantly. This study suggests that concomitant mild to moderate left ventricular failure is not a contra-indication to nicardipine therapy in patients with angina.

DPI 201-106 is a novel compound unrelated to other cardioactive agents and has been shown to have an inotropic effect in animal preparations. The drug was given by intravenous infusion (20 mg over 10 min) to 10 patients with moderate cardiac failure and the haemodynamic effects measured at intervals up to 1 h following infusion. Maximal effects were seen immediately following the infusion of DPI 201-106. Cardiac index showed an increase from baseline 2.72 (0.16) 1 min-1 m-2 to 3.18 (0.21) 1 min-1 m-2 at the end of infusion (P less than 0.001). Subsequent values were not significantly raised. Pulmonary capillary wedge pressure and pulmonary artery pressure fell from 27.6 (3.2) and 36.9 (4.4) to 15.3 (3.6) and 24.2 (4.9) mmHg, respectively (P less than 0.001 in both cases). A statistically significant effect on cardiac index was not seen at 1 h. However, pulmonary pressures remained reduced at this point. Radionuclide ejection fraction showed a significant increase from 15.4 (1.5) to 21.9 (2.2)% (P less than 0.005) at the end of infusion, and maintained a significant increase at 1 h. Having demonstrated beneficial, acute haemodynamic effects in this study, further work should be undertaken with DPI 201-106 to investigate the effect of chronic treatment in patients with cardiac failure.