The molecular mechanisms utilised by mesenchymal stem cells in migration to acute myocardial infarction

Heart damage caused by acute myocardial infarction (AMI) is a leading cause of death and disability in Australia. Novel therapies are still required for the treatment of this condition due to the poor reparative ability of the heart. As such, cellular therapies that assist in the recovery of heart muscle are of great current interest. Culture expanded mesenchymal stem cells (MSC) represent a stem and progenitor cell population that has been shown to promote tissue recovery in pre-clinical studies of AMI. For MSC-based therapies in the clinic, an intravenous route of administration would ideally be used due to the low cost, ease of delivery and relative safety. The study of MSC migration is therefore clinically relevant for a minimally invasive cell therapy to promote regeneration of damaged tissue. C57BL/6, UBI-GFP-BL/6 and CD44-/-/GFP+/+ mice were utilised to investigate mMSC migration. To assist in murine models of MSC migration, a novel method was used for the isolation of murine MSC (mMSC). These mMSC were then expanded in culture and putative mMSC were positive for Sca-1, CD90.2, and CD44 and were negative for CD45 and CD11b. Furthermore, mMSC from C57BL/6 and UBI-GFP-BL/6 mice were shown to differentiate into cells of the mesodermal lineage. Cells from CD44-/-/GFP+/+ mice were positive for Sca-1 and CD90.2, and negative for CD44, CD45 and CD11b however, these cells were unable to differentiate into adipocytes and chondrocytes and express lineage specific genes, PLIN and ACAN. Analysis of mMSC chemokine receptor (CR) expression showed that although mMSC do express chemokine receptors, (including those specific for chemokines released after AMI), these were low or undetectable by mRNA. However, protein expression could be detected, which was predominantly cytoplasmic. It was further shown that in both healthy (unperturbed) and inflamed tissues, mMSC had very little specific migration and engraftment after intravenous injection. To determine if poor mMSC migration was due to the inability of mMSC to respond to chemotactic stimuli, chemokine expression in bone marrow, skin injury and hearts (healthy and after AMI) was analysed at various time points by quantitative real-time PCR (qRT PCR). Many chemokines were up-regulated after skin biopsy and AMI, but the highest acute levels were found for CXCL12 and CCL7. Due to their high expression in infarcted hearts, the chemokines CXCL12 and CCL7 were tested for their effect on mMSC migration. Despite CR expression at both protein and mRNA levels, migration in response to CXCL12 and CCL7 was low in mMSC cultured on Nunclon plastic. A novel tissue culture plastic technology (UpCellTM) was then used that allowed gentle non-enzymatic dissociation of mMSC, thus preserving surface expression of the CRs. Despite this the in vitro data indicated that CXCL12 fails to induce significant migration ability of mMSC, while CCL7 induces significant, but low-level migration. We speculated this may be because of low levels of surface expression of chemokine receptors. In a strategy to increase cell surface expression of mMSC chemokine receptors and enhance their in vitro and in vivo migration capacity, mMSC were pre-treated with pro-inflammatory cytokines. Increased levels of both mRNA and surface protein expression were found for CRs by pre-treating mMSC with pro-inflammatory cytokines including TNF-á, IFN-ã, IL-1á and IL-6. Furthermore, the chemotactic response of mMSC to CXCL12 and CCL7 was significantly higher with these pretreated cells. Finally, the effectiveness of this type of cell manipulation was demonstrated in vivo, where mMSC pre-treated with TNF-á and IFN-ã showed significantly increased migration in skin injury and AMI models. Therefore this thesis has demonstrated, using in vitro and in vivo models, the potential for prior manipulation of MSC as a possible means for increasing the utility of intravenously delivery for MSC-based cellular therapies.

Renal bioenergetics during early gram-negative mammalian sepsis and angiotensin II infusion

Purpose: To measure renal adenosine triphosphate (ATP) (bioenergetics) during hypotensive sepsis with or without angiotensin II (Ang II) infusion. Methods: In anaesthetised sheep implanted with a renal artery flow probe and a magnetic resonance coil around one kidney, we induced hypotensive sepsis with intravenous Escherichia coli injection. We measured mean arterial pressure (MAP), heart rate, renal blood flow RBF and renal ATP levels using magnetic resonance spectroscopy. After 2 h of sepsis, we randomly assigned sheep to receive an infusion of Ang II or vehicle intravenously and studied the effect of treatment on the same variables. Results: After E. coli administration, the experimental animals developed hypotensive sepsis (MAP from 92 ± 9 at baseline to 58 ± 4 mmHg at 4 h). Initially, RBF increased, then, after 4 h, it decreased below control levels (from 175 ± 28 at baseline to 138 ± 27 mL/min). Despite decreased RBF and hypotension, renal ATP was unchanged (total ATP to inorganic phosphate ratio from 0.69 ± 0.02 to 0.70 ± 0.02). Ang II infusion restored MAP but caused significant renal vasoconstriction. However, it induced no changes in renal ATP (total ATP to inorganic phosphate ratio from 0.79 ± 0.03 to 0.80 ± 0.02). Conclusions:During early hypotensive experimental Gram-negative sepsis, there was no evidence of renal bioenergetic failure despite decreased RBF. In this setting, the addition of a powerful renal vasoconstrictor does not lead to deterioration in renal bioenergetics.

The effect of oral metformin on insulin sensitivity in insulin-resistant ponies

Metformin may be an effective therapeutic option for insulin-resistant (I-R) horses/ponies because, in humans, it reportedly enhances insulin sensitivity (SI) of peripheral tissues without stimulating insulin secretion. To determine the effect of metformin on insulin and glucose dynamics in I-R ponies, six ponies were studied in a cross-over design by Minimal Model analysis of a frequently-sampled intravenous glucose tolerance test (FSIGT). Metformin was administered at 15. mg/kg bodyweight (BW), orally, twice-daily, for 21. days to the metformin-treated group. The control group received a placebo. A FSIGT was conducted before and after treatment. The Minimal Model of glucose and insulin dynamics rendered indices describing SI, glucose effectiveness (Sg), acute insulin response to glucose (AIRg) and the disposition index (DI). The body condition score (BCS), BW and cresty neck score (CNS) were also assessed. There was no significant change in SI, Sg, AIRg, DI, BW, BCS or CNS in response to metformin, or over time in the control group. There were no measurable benefits of metformin on SI, consistent with recent work showing that the bioavailability of metformin in horses is poor, and chronic dosing may not achieve therapeutic blood concentrations. Alternatively, metformin may only be effective in obese ponies losing weight or with hyperglycaemia.

Drugs and neurotransmitters

This eChapter has an introduction to pharmacology and drug nomenclature followed by a detailed discussion of routes of administration starting with oral administration (with absorption from the gastrointestinal tract, and first pass liver metabolism. This is followed by a discussion of rectal, sublingual and injection routes of administration(intravenous, intra-arterial, subcutaneous, intramuscular, intrathecal and epidural). Then the topical, pulmonary and intraosseus routes of administration are considered.

The use of hypnosis in labor and delivery : a preliminary study

Self-hypnosis was taught to 87 obstetric patients (HYP) and was not taught to 56 other patients (CNTRL), all delivered by the same family physician, in order to determine whether the use of self-hypnosis by low-risk obstetric patients leads to fewer technologic interventions during their deliveries or greater satisfaction of parturients with their delivery experience or both. The outcomes of the deliveries of these two groups were compared, and the HYP group was compared to 352 low-risk patients delivered by other family physicians at the same hospital (WCH). Questionnaires were mailed postpartum to 156 patients, all delivered by the same family physician, to determine satisfaction with delivery using the Labor and Delivery Satisfaction Index (LADSI). The hypnosis group showed a significant reduction in the number of epidurals (11.4% less than CNTRL and 17.9% less than WCH, p < 0.05) and the use of intravenous lines (18.5% less for both, p < 0.05). The number of episiotomies was significantly less in the HYP group compared to WCH (15.9%, p < 0.05) and 11.5% less when compared to CNTRL. The tear rate was not statistically different. Combined use of the intervention triad (epidural–forceps–episiotomy) was less for HYP than for CNTRL (15.8% less) and WCH (10.2% less, p < 0.05). More deliveries were done in the labor room with HYP than CNTRL (21%, p < 0.05). The second stage was shortened by 10 min (HYP vs CNTRL). Overall satisfaction of HYP and CNTRL patients was similar and generally favorable.

Blood cultures for evaluation of early postoperative fever after femoral neck fracture surgery

PURPOSE. To evaluate the utility of blood cultures in the assessment of early postoperative fever in hip fracture patients with no other indicators of sepsis. METHODS. 101 blood cultures were drawn on postoperative days 0 to 5 to investigate 84 febrile episodes in 31 women and 30 men (mean age, 80 years) whose body temperature measured via the tympanic route was ≥38ºC. Culture results of these 61 patients were divided into culture-positive and culture-negative groups for comparison. RESULTS. Of the 101 blood cultures, only 2 were positive: one was obtained 5 days after dynamic hip screw fixation, and the other 4 days after hemiarthroplasty. Both blood cultures grew coagulase-negative staphylococcal species, which were deemed to be skin contaminants not requiring change of patient management. 44 of these patients were treated with oral or intravenous antibiotics for a period of time. CONCLUSION. The risk of bacteraemia in patients with postoperative fever but no other symptoms of infection is low. Routine procurement of blood cultures in such patients is ineffective and of limited utility.

Clinically-indicated replacement versus routine replacement of peripheral venous catheters

BACKGROUND: US Centers for Disease Control guidelines recommend replacement of peripheral intravenous (IV) catheters no more frequently than every 72 to 96 hours. Routine replacement is thought to reduce the risk of phlebitis and bloodstream infection. Catheter insertion is an unpleasant experience for patients and replacement may be unnecessary if the catheter remains functional and there are no signs of inflammation. Costs associated with routine replacement may be considerable. This is an update of a review first published in 2010. OBJECTIVES: To assess the effects of removing peripheral IV catheters when clinically indicated compared with removing and re-siting the catheter routinely. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases (PVD) Group Trials Search Co-ordinator searched the PVD Specialised Register (December 2012) and CENTRAL (2012, Issue 11). We also searched MEDLINE (last searched October 2012) and clinical trials registries. SELECTION CRITERIA: Randomised controlled trials that compared routine removal of peripheral IV catheters with removal only when clinically indicated in hospitalised or community dwelling patients receiving continuous or intermittent infusions. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: Seven trials with a total of 4895 patients were included in the review. Catheter-related bloodstream infection (CRBSI) was assessed in five trials (4806 patients). There was no significant between group difference in the CRBSI rate (clinically-indicated 1/2365; routine change 2/2441). The risk ratio (RR) was 0.61 but the confidence interval (CI) was wide, creating uncertainty around the estimate (95% CI 0.08 to 4.68; P = 0.64). No difference in phlebitis rates was found whether catheters were changed according to clinical indications or routinely (clinically-indicated 186/2365; 3-day change 166/2441; RR 1.14, 95% CI 0.93 to 1.39). This result was unaffected by whether infusion through the catheter was continuous or intermittent. We also analysed the data by number of device days and again no differences between groups were observed (RR 1.03, 95% CI 0.84 to 1.27; P = 0.75). One trial assessed all-cause bloodstream infection. There was no difference in this outcome between the two groups (clinically-indicated 4/1593 (0.02%); routine change 9/1690 (0.05%); P = 0.21). Cannulation costs were lower by approximately AUD 7.00 in the clinically-indicated group (mean difference (MD) -6.96, 95% CI -9.05 to -4.86; P ≤ 0.00001). AUTHORS' CONCLUSIONS: The review found no evidence to support changing catheters every 72 to 96 hours. Consequently, healthcare organisations may consider changing to a policy whereby catheters are changed only if clinically indicated. This would provide significant cost savings and would spare patients the unnecessary pain of routine re-sites in the absence of clinical indications. To minimise peripheral catheter-related complications, the insertion site should be inspected at each shift change and the catheter removed if signs of inflammation, infiltration, or blockage are present. OBJECTIVES: To assess the effects of removing peripheral IV catheters when clinically indicated compared with removing and re-siting the catheter routinely. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases (PVD) Group Trials Search Co-ordinator searched the PVD Specialised Register (December 2012) and CENTRAL (2012, Issue 11). We also searched MEDLINE (last searched October 2012) and clinical trials registries. SELECTION CRITERIA: Randomised controlled trials that compared routine removal of peripheral IV catheters with removal only when clinically indicated in hospitalised or community dwelling patients receiving continuous or intermittent infusions. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: Seven trials with a total of 4895 patients were included in the review. Catheter-related bloodstream infection (CRBSI) was assessed in five trials (4806 patients). There was no significant between group difference in the CRBSI rate (clinically-indicated 1/2365; routine change 2/2441). The risk ratio (RR) was 0.61 but the confidence interval (CI) was wide, creating uncertainty around the estimate (95% CI 0.08 to 4.68; P = 0.64). No difference in phlebitis rates was found whether catheters were changed according to clinical indications or routinely (clinically-indicated 186/2365; 3-day change 166/2441; RR 1.14, 95% CI 0.93 to 1.39). This result was unaffected by whether infusion through the catheter was continuous or intermittent. We also analysed the data by number of device days and again no differences between groups were observed (RR 1.03, 95% CI 0.84 to 1.27; P = 0.75). One trial assessed all-cause bloodstream infection. There was no difference in this outcome between the two groups (clinically-indicated 4/1593 (0.02%); routine change 9/1690 (0.05%); P = 0.21). Cannulation costs were lower by approximately AUD 7.00 in the clinically-indicated group (mean difference (MD) -6.96, 95% CI -9.05 to -4.86; P ≤ 0.00001). AUTHORS' CONCLUSIONS: The review found no evidence to support changing catheters every 72 to 96 hours. Consequently, healthcare organisations may consider changing to a policy whereby catheters are changed only if clinically indicated. This would provide significant cost savings and would spare patients the unnecessary pain of routine re-sites in the absence of clinical indications. To minimise peripheral catheter-related complications, the insertion site should be inspected at each shift change and the catheter removed if signs of inflammation, infiltration, or blockage are present.

The clinical effectiveness of interventions to assist perioperative temperature management for women undergoing Cesarean Section : a systematic review

Background Women undergoing Cesarean Section (CS) are vulnerable to the adverse effects associated with perioperative core temperature drop, in part due to the tendency for CS to be performed under neuraxial anesthesia, blood and fluid loss, and vasodilation. Inadvertent perioperative hypothermia (IPH) is a common condition that affects patients undergoing surgery of all specialties and is detrimental to all age groups, including neonates. Previous systematic reviews on IPH prevention largely focus on either adult or all ages populations, and have mainly overlooked pregnant or CS patients as a distinct group. Not all recommendations made by systematic reviews targeting all adult patients may be transferable to CS patients. Alternative, effective methods for preventing or managing hypothermia in this group would be valuable. Objectives To synthesize the best available evidence in relation to preventing and/or treating hypothermia in mothers after CS surgery. Types of participants Adult patients over the age of 18 years, of any ethnic background, with or without co-morbidities, undergoing any mode of anesthesia for any type of CS (emergency or planned) at healthcare facilities who have received interventions to limit or manage perioperative core heat loss were included. Types of intervention(s) Active or passive warming methods versus usual care or placebo, that aim to limit or manage core heat loss as applied to women undergoing CS were included. Types of studies Randomized controlled trials (RCTs) that met the inclusion criteria, with reduction of perioperative hypothermia a primary or secondary outcome were considered. Types of outcomes Primary outcome: maternal core temperature measured during the preoperative, intraoperative and postoperative phases of care Secondary outcomes: newborn core temperature at birth, umbilical pH obtained immediately after birth, Apgar scores, length of Post Anesthetic Care Unit (PACU) stay, maternal thermal comfort. Search strategy A comprehensive search was undertaken of the following databases from their inception until May 2012: ProQuest, Web of Science, Scopus, Dissertation and Theses PQDT (via ProQuest), Current Contents, CENTRAL, Mednar, OpenGrey, Clinical Trials. There were no language restrictions. Methodological quality Retrieved papers were assessed for methodological quality by two independent reviewers prior to inclusion using JBI software. Disagreements were resolved via consultation with the third reviewer. An assessment of quality of the included papers was also made in relation to five key quality factors. Data collection Two independent reviewers extracted data from the included papers using a previously piloted customized data extraction tool. Results 12 studies with a combined total of 719 participants were included. Three broad intervention groups were identified; intravenous (IV) fluid warming, warming devices, leg wrapping. IV fluid warming, whether administered intraoperatively or preoperatively, was found to be effective at maintaining maternal (but not neonatal) temperature and preventing shivering, but does not improve thermal comfort. The effectiveness of IV fluid warming on Apgar scores and umbilical pH remains unclear. Warming devices, including forced air warming and under body carbon polymer mattresses, were effective at preventing hypothermia and reduced shivering, however were most effective if applied preoperatively. The effectiveness of warming devices to improve thermal comfort remains unclear. Preoperative forced air warming appears to aid maintenance of neonatal temperature, while intraoperative forced air warming does not. Forced air warming was not effective at improving Apgar scores and the effects for umbilical pH remain unclear. Conclusions Intravenous fluid warming, by any method, improves maternal temperature and reduces shivering for women undergoing CS. Preoperative body warming devices also improve maternal temperature, in addition to reducing shivering.

Comparison of diagnostic tests in myasthenia gravis

Results of 3 tests, intravenous edrophonium chloride, EMG, and acetylcholine receptor antibody testing, were compared in patients with generalised and ocular myasthenia gravis. None of the 3 tests was positive in any patient with a diagnosis other than myasthenia. However, equivocal results were obtained with edrophonium and EMG testing in some patients with myasthenia gravis and in patients with other diseases. It is concluded from this survey that antibody and edrophonium testing were equally efficient in detecting generalised myasthenia gravis. Edrophonium testing was superior in ocular myasthenia gravis. Although the yields from each test varied, all 3 tests were needed for the evaluation of some myasthenia gravis patients as each test may provide additional information.

Identification of radiological alveolar pneumonia in children with high rates of hospitalized respiratory infections : Comparison of WHO-defined and pediatric pulmonologist diagnosis in the clinical context

Background A reliable standardized diagnosis of pneumonia in children has long been difficult to achieve. Clinical and radiological criteria have been developed by the World Health Organization (WHO), however, their generalizability to different populations is uncertain. We evaluated WHO defined chest radiograph (CXRs) confirmed alveolar pneumonia in the clinical context in Central Australian Aboriginal children, a high risk population, hospitalized with acute lower respiratory illness (ALRI). Methods CXRs in children (aged 1-60 months) hospitalized and treated with intravenous antibiotics for ALRI and enrolled in a randomized controlled trial (RCT) of Vitamin A/Zinc supplementation were matched with data collected during a population-based study of WHO-defined primary endpoint pneumonia (WHO-EPC). These CXRs were reread by a pediatric pulmonologist (PP) and classified as pneumonia-PP when alveolar changes were present. Sensitivities, specificities, positive and negative predictive values (PPV, NPV) for clinical presentations were compared between WHO-EPC and pneumonia-PP. Results Of the 147 episodes of hospitalized ALRI, WHO-EPC was significantly less commonly diagnosed in 40 (27.2%) compared to pneumonia-PP (difference 20.4%, 95% CI 9.6-31.2, P < 0.001). Clinical signs on admission were poor predictors for both pneumonia-PP and WHO-EPC; the sensitivities of clinical signs ranged from a high of 45% for tachypnea to 5% for fever + tachypnea + chest-indrawing. The PPV range was 40-20%, respectively. Higher PPVs were observed against the pediatric pulmonologist's diagnosis compared to WHO-EPC. Conclusions WHO-EPC underestimates alveolar consolidation in a clinical context. Its use in clinical practice or in research designed to inform clinical management in this population should be avoided. Pediatr Pulmonol. 2012; 47:386-392. (C) 2011 Wiley Periodicals, Inc.

A phase II study of mitomycin C and oral etoposide for advanced adenocarcinoma of the upper gastrointestinal tract

Background: Mitomycin C and etoposide have both demonstrated activity against gastric carcinoma. Etoposide is a topoisomerase II inhibitor with evidence for phase-specific and schedule-dependent activity. Patients and method. Twenty-eight consecutive patients with advanced upper gastrointestinal adenocarcinoma were treated with intravenous (i.v.) bolus mitomycin C 6 mg/m2 on day 1 every 21 days to a maximum of four courses. Oral etoposide capsules 50 mg b.i.d. (or 35 mg b.i.d. liquid) were administered days 1 to 10 extending to 14 days in subsequent courses if absolute neutrophil count >1.5 x 109/l on day 14 of first course, for up to six courses. Results: Twenty-six patients were assessed for response of whom 12 had measurable disease and 14 evaluable disease. Four patients had a documented response (one complete remission, three partial remissions) with an objective response rate of 15% (95% confidence interval (95% CI) 4%-35%). Eight patients had stable disease and 14 progressive disease. The median survival was six months. The schedule was well tolerated with no treatment-related deaths. Nine patients experienced leucopenia (seven grade II and two grade III). Nausea and vomiting (eight grade II, one grade III), fatigue (eight grade II, two grade III) and anaemia (seven grade II, two grade III) were the predominant toxicities. Conclusion: This out-patient schedule is well tolerated and shows modest activity in the treatment of advanced upper gastrointestinal adenocarcinoma. Further studies using protracted schedules of etoposide both orally and as infusional treatment should be developed.

A randomised, concentration-controlled, comparison of standard (5-day) vs. prolonged (15-day) infusions of etoposide phosphate in small-cell lung cancer

Purpose: This randomised trial was designed to investigate the activity and toxicity of continuous infusion etoposide phosphate (EP), targeting a plasma etoposide concentration of either 3 μg/ml for five days (5d) or 1 μg/ml for 15 days (15d), in previously untreated SCLC patients with extensive disease. Patients and methods: EP was used as a single agent. Plasma etoposide concentration was monitored on days 2 and 4 in patients receiving 5d EP and on days 2, 5, 8 and 11 in patients receiving 15d EP, with infusion modification to ensure target concentrations were achieved. Treatment was repeated every 21 days for up to six cycles, with a 25% reduction in target concentration in patients with toxicity. Results: The study has closed early after entry of 29 patients (14 with 5d EP, 15 with 15d EP). Objective responses were seen in seven of 12 (58%, confidence interval (CI): 27%-85%) evaluable patients after 5d EP, and two of 14 (14%, CI: 4%42%) evaluable patients after 15d EP (P = 0.038). Grade 3 or 4 neutropenia or leucopenia during the first cycle of treatment was observed in six of 12 patients after 5d EP and 0/14 patients after 15d EP (P = 0.004), with median nadir WBC count of 2.6 x 109/1 after 5d and 5.0 x 109/1 after 15d EP (P = 0.017). Only one of 49 cycles of 15d EP was associated with grade 3 or worse haematological toxicity, compared to 14 of 61 cycles of 5d EP. Conclusions: Although the number of patients entered into this trial was small, the low activity seen at 1 μg/ml in the 15d arm suggests that this concentration is below the therapeutic window in this setting. Further concentration- controlled studies with prolonged EP infusions are required.

A metastatic neuroendocrine anaplastic small cell tumor in a patient with multiple endocrine neoplasia type 1 syndrome : assessment of disease status and response to doxorubicin, cyclophosphamide, etoposide chemotherapy through scintigraphic imaging with 111In-pentetreotide

Extrapulmonary small cell and small cell neuroendocrine tumors of unknown primary site are, in general, aggressive neoplasms with a short median survival. Like small cell lung cancer (SCLC), they often are responsive to chemotherapy and radiotherapy. Small cell lung cancer and well differentiated neuroendocrine carcinomas of the gastrointestinal tract and pancreas tend to express somatostatin receptors. These tumors may be localized in patients by scintigraphic imaging using radiolabeled somatostatin analogues. A patient with an anaplastic neuroendocrine small cell tumor arising on a background of multiple endocrine neoplasia type 1 syndrome is reported. The patient had a known large pancreatic gastrinoma and previously treated parathyroid adenopathy. At presentation, there was small cell cancer throughout the liver and skeleton. Imaging with a radiolabeled somatostatin analogue, 111In- pentetreotide (Mallinckrodt Medical B. V., Petten, Holland), revealed all sites of disease detected by routine biochemical and radiologic methods. After six cycles of chemotherapy with doxorubicin, cyclophosphamide, and etoposide, there was almost complete clearance of the metastatic disease. 111In-pentetreotide scintigraphy revealed uptake consistent with small areas of residual disease in the liver, the abdomen (in mesenteric lymph nodes), and posterior thorax (in a rib). The primary gastrinoma present before the onset of the anaplastic small cell cancer showed no evidence of response to the treatment. The patient remained well for 1 year and then relapsed with brain, lung, liver, and skeletal metastases. Despite an initial response to salvage radiotherapy and chemotherapy with carboplatin and dacarbazine, the patient died 6 months later.

A phase II study of the modulation of 5-fluorouracil and folinic acid with high-dose infusional hydroxyurea in metastatic colorectal carcinoma

Background: Hydroxyurea (HU), an inhibitor of ribonucleotide reductase, may potentiate the activity of 5-fluorouracil (5-FU) and folinic acid (FA) by reducing the deoxyribonucleotide pool available for DNA synthesis and repair. However as HU may inhibit the formation of 5-fluoro-2-deoxyuridine-5- monophosphate (FdUMP), one of the principal active metabolites of 5-FU, the scheduling of HU may be critical. In vitro experiments suggest that administration of HU following 5-FU, maintaining the concentration in the region of I mM for six or more hours, significantly enhances the efficacy of 5-FU. Patients and methods: 5-FU/FA was given as follows: days 1 and 2 - FA 250 mg/m 2 (max. 350 mg) over two hours followed by 5-FU 400 mg/m 2 by intravenous bolus (ivb) over 15 minutes and subsequently 5-FU 400 mg/m 2 infusion (ivi) over 22 hours. HU was administered on day 3 immediately after the 5-FU with 3 g ivb over 15 minutes followed by 12 g ivi over 12 hours. Results: Thirty patients were entered into the study. Median survival was nine months (range 1-51 + months). There were eight partial responses (28%, 95% CI: 13%-47%). The median duration of response was 6.5 (range 4-9 months). Grade 3-4 toxicities included neutropenia (grade 3 in eight patients and grade 4 in five), anaemia (grade 3 in one patient) and diarrhoea (grade 3 in two patients). Neutropenia was associated with pyrexia in two patients. Phlebitis at the infusion site occurred in five patients. The treatment was complicated by pulmonary embolism in one patient and deep venous thrombosis in another. Conclusion: HU administered in this schedule is well tolerated. Based on these results and those of other phase II studies, a randomised phase III study of 5-FU, FA and HU versus 5-FU and FA using the standard de Gramont schedule is recommended.

A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

The aims of this phase I study were to establish the maximum tolerated dose, safety profile and activity of liposomal daunorubicin, DaunoXome (NeXstar Pharmaceuticals), in the treatment of metastatic breast cancer. DaunoXome was administered intravenously over 2 h in 21 day cycles and doses were increased from 80 to 100, 120 and 150 mg m 2. Sixteen patients were enrolled. A total of 70 cycles of DaunoXome were administered. The maximum tolerated dose was 120 mg m 2, the dose-limiting toxicity being prolonged grade 4 neutropenia or neutropenic pyrexia necessitating dose reductions at 120 and 150 mg m 2. Asymptomatic cardiotoxicity was observed in three patients: grade 1 in one treated with a cumulative dose of 800 mg m 2 and grade 2 in two, one who received a cumulative dose of 960 mg m 2 and the other a cumulative dose of 600 mg m 2 with a previous neoadjuvant doxorubicin chemotherapy of 300 mg m 2. Tumour response was evaluable in 15 patients, of whom two had objective responses, six had stable disease and seven had progressive disease. In conclusion, DaunoXome is associated with mild, manageable toxicities and has anti-tumour activity in metastatic breast cancer. The findings support further phase II evaluation of DaunoXome alone and in combination with other standard non-anthracycline cytotoxic or novel targeted agents. Although the dose-limiting toxicity for DaunoXome was febrile neutropenia at 120 mg m 2, we would recommend this dose for further evaluation, as the febrile neutropenia occurred after four or more cycles in three of the four episodes seen, was short lived and uncomplicated. © 2002 Cancer Research UK.