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Steen Lindkær-Jensen,1 Stig Larsen,2 Nina Habib-Lindkær-Jensen,1 Hans E Fagertun3 1Department of Surgery and Cancer, Hammersmith Hospital Campus, Imperial College, London, UK; 2Center of Epidemiology and Biostatistics, Faculty of Veterinary Medicine, University of Life Science, Oslo, Norway; 3Meddoc Research AS, Skjetten, Norway Abstract: A benzene-poly-carboxylic acid complex with cis-diammineplatinum(II) dihydrocholride, BP-C1 is currently used in clinical trials in treating metastatic breast cancer. BP-C1 controls tumor growth with a few mild side-effects, improving quality of life.Methods: The data consisted of prospectively collected laboratory results from 47 patients in two controlled clinical trials of daily intramuscular injections of BP-C1 for 32 days. Study I was performed as an open, nonrandomized, Phase I dose–response, multicenter study with a three-level, between-patient, response surface pathway design. The second study was a randomized, double-blind, and placebo-controlled, multicenter study with a stratified semi-crossover design.Results: Hemoglobin (Hb) and hematocrit (Hct) increased significantly (P

Stig Larsen,1 Kritiya Butthongkomvong,2 Alexey Manikhas,3 Ekaterina Trishkina,4 Elena Poddubuskaya,5 Marina Matrosova,6 Vichien Srimuninnimit,7 Steen Lindkær-Jensen81Department of Controlled Clinical Trials and Biostatistics, Centre for Epidemiology and Biostatistics, University of Life Science, Oslo, Norway; 2Udonthani Cancer Hospital, Udonthani, Thailand; 3Department of Oncology, City Clinical Oncology, Dispensary, St Petersburg, Russia; 4Department of Oncology, Leningrad Regional Oncology Centre, St Petersburg, Russia; 5Department of Oncology, Unit of Russian Academy of Medical Science, Moscow, Russia; 6Department of Oncology, N Novgorod Regional Oncology Dispensary, Novgorod, Russia; 7Division of Medical Oncology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; 8Department of Surgery and Cancer, Imperial College, Hammersmith Hospital, London, UKAbstract: The aims were to compare the efficacy and tolerability of a new benzene-poly-carboxylic acids complex with cis-diammineplatinum (II) dichloride (BP-C1) versus placebo and to investigate the long-term tolerability of BP-C1 in the treatment of patients with metastatic breast cancer.Material and methods: A randomized, double-blind, placebo-controlled multicenter study was performed with a semi-crossover design. Patients allocated to placebo switched to BP-C1 after 32 days of treatment. Patients who completed 32 days of BP-C1 treatment were offered the opportunity to continue on BP-C1 for an additional 32 days in an open-label extension. Patients were then followed up for another 28 days. Thirty patients were given daily intramuscular injections of 0.035 mg/kg of body weight BP-C1 or placebo for 32 days. Biochemistry, hematology, National Cancer Institute Common Terminology Criteria for Adverse Events (CTC-NCI), European Organisation for Research and Treatment of Cancer quality of life questionnaire (QOL-C30 and the breast-cancer–specific BR23) data were recorded at screening and after every 16 days of treatment. Computed tomography was performed at screening and every 32 days.Results: The sum of target lesions increased 2.4% in the BP-C1 group and 14.3% in the placebo group. Only the increase in the placebo group was significant (P=0.013). The difference between the groups was significant in favor of BP-C1 (P=0.04). There was a significant difference (P=0.026) in favor of BP-C1 regarding Response Evaluation Criteria In Solid Tumors (RECIST) classification. The sum of lesions increased slightly in the patients receiving 64 days of continuous BP-C1 treatment, of whom 68.4% were classified as responders. The sum CTC-NCI toxicity score increased nonsignificantly in the BP-C1 group but significantly in the placebo group (P=0.05). The difference in increase between groups did not meet the level of significance (P=0.12). The sum toxicity score was reduced in the patients receiving 64 days of BP-C1 from 9.2 at screening to 8.9 at Day 48, but it increased again to 10.1 by Day 64 and 10.6 during the 28-day follow-up. "Breast cancer-related pain and discomfort" and "Breast cancer treatment problem last week" were significantly reduced (P=0.02) in the BP-C1 group but increased slightly in the placebo group; between-group differences were significant in favor of BP-C1 (P=0.05). "Breast cancer related pain and discomfort", "Breast cancer treatment problem last week," and "Physical activity problem" were significantly reduced during the 64 days of BP-C1 treatment (P≤0.05).Conclusion: For patients suffering from stage IV metastatic breast cancer, treatment with BP-C1 reduces cancer growth, is well tolerated, improves quality of life, and produces few adverse events, which were mainly mild and manageable.Keywords: tumor growth reduction, improved Quality of Life, safe, few transient adverse effects

Sagita Dewi,1 Veronica Kristiansen,2 Steen Lindkær-Jensen,3,4 Stig Larsen1 1Centre for Epidemiology and Biostatistics, Faculty of Veterinary Medicine and Biosciences, Norwegian University of Life Sciences, Ås, Norway; 2Department of Companion Animal Sciences, Faculty of Veterinary Medicine and Biosciences, Norwegian University of Life Sciences, Oslo, Norway; 3Department of Surgery and Cancer, Hammersmith Hospital Campus, Imperial College, Du Cane Road, London, UK; 4Meabco A/S, Copenhagen, Denmark Background: The most commonly used escalation methods in dose-finding studies have obvious weaknesses, and the Bayesian approach is difficult for clinicians to understand and to apply. The study aims were to introduce and assess the performance of clinically based response surface pathway (RSP) design for dose-finding studies, exemplified by one between-patient study, one within-patient study, and simulation studies. Methods: The between-patient study consisted of 15 women suffering from stage IV breast cancer, while the within-patient study consisted of seven female dogs with metastatic mammary cancer. The studies were conducted to determine the maximum tolerated dose (MTD) of a new anticancer agent named BP-C1 using three-level RSP designs. Adjustment of the dose from one design level to the next was based on a k-adjustment factor estimated to ensure coverage of the entire predefined dose window. Patient sequences with an equal number of patients as design levels were included in the between-patient design, whereas the same patients were included in all the design levels in the within-patient design. Results: Four of the five patient sequences in the between-patient study and all seven dogs in the within-patient study reached the upper limit of the dose windows without any increase in toxicity. The MTD of BP-C1 was thus found to be higher than the predefined cumulative dose window for both patient groups. In all three scenarios, the RSP design estimated MTDs better than the traditional 3+3 design; however, the toxicity rates were found to be higher when the target MTD was under the starting dose. Conclusion: The RSP designs do not need an assumed statistical model, and may be useful in estimating MTD, using a minimal sample size. The k-adjustment factor ensures complete dose window coverage and the design utilizes more information by allowing multinomial outcomes. Keywords: dose escalation procedure, maximum tolerated dose, MTD, phase I clinical trial, RSP

Larsen S, Butthongkomvog K, Manikhas A, et al. Breast Cancer: Targets and Therapy. 2014;6:179–189.On page 184 there is an error in Figure 3A. The error consists of a yellow bar at +16 days in the placebo group. Read the original article

The pharmacokinetic profile, tolerability and efficacy of benzene-poly-carboxylic acids complex with cis-diammineplatinum ( II) dichloride ( BP-C1) were studied in dogs with mammary cancer. A three-level response surface pathway designed trial was performed on seven dogs. At each level BP-C1 was administered subcutaneously daily for 7 days followed by a 7-day rest period in a dose escalating manner. Adverse events according to VCOG-CTCAE, performance status and tumour progression were recorded. The pharmacokinetic profile followed a two-compartment model with rapid absorption, short distribution, and a slow elimination phase. The overall elimination half-life was 125 h. The maximum tolerated dose of BP-C1 was estimated to be above 0.46 mg kg−1. A significant reduction in VCOG-CTCAE toxicity which correlated negatively with increasing dose was found. The dogs' general performance status remained unchanged. No decrease in total tumour burden was found, although temporary tumour reduction was seen in some target tumours. [ABSTRACT FROM AUTHOR]

Some cases of breast cancer are composed of clones of hormonal-independent growing cells, which do not respond to therapy. In the present study, the effect of Benzene-Poly-Carboxylic Acid Complex (BP-C1) on growth of human breast-cancer cells was tested. BP-C1 is a novel anti-cancer complex of benzene-poly-carboxylic acids with a very low concentration of cis-diammineplatinum (II) dichloride. Human breast cancer cells, MCF-7 and T47D, were used. Cell viability was detected by XTT assay and apoptosis was detected by Flow Cytometry and by annexin V/FITC/PI assay. Caspases were detected by western blot analysis and gene expression was measured by using the Applied Biosystems® TaqMan® Array Plates. The results showed that exposure of the cells to BP-C1 for 48 h, significantly (P<0.001) reduced cell viability, induced apoptosis and activated caspase 8 and caspace 9. Moreover, gene expression experiments indicated that BP-C1 increased the expression of pro-apoptotic genes (CASP8AP1, TNFRSF21, NFkB2, FADD, BCL10 and CASP8) and lowered the level of mRNA transcripts of inhibitory apoptotic genes (BCL2L11, BCL2L2 and XIAP. These findings may lead to the development of new therapeutic strategies for treatment of human cancer using BP-C1 analog.

Unlabelled: Hepatocellular carcinoma (HCC) occurs predominantly in patients with liver cirrhosis. Here we show an innovative RNA-based targeted approach to enhance endogenous albumin production while reducing liver tumor burden. We designed short-activating RNAs (saRNA) to enhance expression of C/EBPα (CCAAT/enhancer-binding protein-α), a transcriptional regulator and activator of albumin gene expression. Increased levels of both C/EBPα and albumin mRNA in addition to a 3-fold increase in albumin secretion and 50% decrease in cell proliferation was observed in C/EBPα-saRNA transfected HepG2 cells. Intravenous injection of C/EBPα-saRNA in a cirrhotic rat model with multifocal liver tumors increased circulating serum albumin by over 30%, showing evidence of improved liver function. Tumor burden decreased by 80% (P = 0.003) with a 40% reduction in a marker of preneoplastic transformation. Since C/EBPα has known antiproliferative activities by way of retinoblastoma, p21, and cyclins, we used messenger RNA (mRNA) expression liver cancer-specific microarray in C/EBPα-saRNA-transfected HepG2 cells to confirm down-regulation of genes strongly enriched for negative regulation of apoptosis, angiogenesis, and metastasis. Up-regulated genes were enriched for tumor suppressors and positive regulators of cell differentiation. A quantitative polymerase chain reaction (PCR) and western blot analysis of C/EBPα-saRNA-transfected cells suggested that in addition to the known antiproliferative targets of C/EBPα, we also observed suppression of interleukin (IL)6R, c-Myc, and reduced STAT3 phosphorylation., Conclusion: A novel injectable saRNA-oligonucleotide that enhances C/EBPα expression successfully reduces tumor burden and simultaneously improves liver function in a clinically relevant liver cirrhosis/HCC model., (© 2013 by the American Association for the Study of Liver Diseases.)

Magnesium sulfate given orally in a hypertonic or isotonic solution did not alter the absorption of therapeutic doses of acetylsalicylic acid or lithium carbonate, despite a purgative effect in 10 volunteers. The concentration of magnesium in serum remained unchanged during the experiments.

In six pigs the gastric concentrations in the pancreaticoduodenal vein were slightly, but significantly, higher than in the carotid artery (p < 0.05). After instillation of meat extract into the duodenal pouches the gastrin concentrations in the pancreaticoduodenal vein increased significantly (p < 0.05), whereas the corresponding arterial concentrations remained almost unchanged. In four pigs the gastrin concentrations remained unchanged in the regional veins and equalled those in the carotid arteries after meat extract installation into jejunal and ileal pouches. Instillation of meat extract into duodenal pouches (three pigs), jejunal pouches (three pigs), and jejunal + ileal pouches (two pigs) caused substantial increase of gastrin concentrations in the regional antral veins (right gastroepiploic veins), whereas no increase was detected after instillation of meat extract into ileal pouches (three pigs). It is concluded that the duodenum in anaesthetized pigs released gastrin, whereas neither the jejunum nor the ileum does. However, an antral release of gastrin may result from duodenal and jejunal protein meal stimulation. The mechanism of this duodeno- and jejuno-antral release is still unknown.

Copper sulfate, given orally in an emetic dose, decreased the absorption of therapeutic doses of acetylsalicylic acid or lithium carbonate, more than was expected judging from the recovery of salicylic acid in the vomit. Ten volunteers participated.

Peripheral hyperinsulinaemia is the cause of metabolic changes that might contribute to the high incidence of macrovascular disease in patients with diabetes mellitus. In order to test this hypothesis muscle biopsies from 12 Type 2 diabetic patients and 14 age and sex matched non-diabetic patients, undergoing minor surgery, were obtained. The diabetic patients had significantly elevated fasting serum insulin (0.29 +/- 0.05 vs 0.06 +/- 0.03 nmol-1) and glucose (8.3 +/- 1.5 vs 4.6 +/- 0.5 mmol-1) and HbA1 levels (8.4 +/- 0.4 vs 5.0 +/- 0.2 per cent). The fasting and 2-h postprandial C-peptide levels were 0.99 +/- 0.25 vs 0.39 +/- 0.12 and 3.12 +/- 0.75 vs 1.09 +/- 0.34 nmol/l, respectively. The diabetic patients showed a marked elevation of triglyceride in the striated muscle biopsies compared to the non-diabetic controls (290 +/- 52 vs 48 +/- 6 mumol/g wet weight, p less than 0.001). Moreover, the activities of glucose-6-phosphate dehydrogenase (0.25 +/- 0.03 vs 0.13 +/- 0.01 U/g wet weight) and malic enzyme (0.15 +/- 0.01 vs 0.05 +/- 0.01 U/g wet weight), necessary for lipid synthesis, were significantly increased (both p less than 0.001) in the diabetic patients while the glycolytic enzymes, hexokinase (0.65 +/- 0.09 vs 1.82 +/- 0.11 U/g wet weight), pyruvate kinase (7.3 +/- 0.9 vs 13.2 +/- 0.9 U/g wet weight), phosphofructokinase (1.3 +/- 0.2 vs 2.6 +/- 0.2 U/g wet weight), and alpha-glycerophosphate dehydrogenase (7.3 +/- 0.5 vs 12.5 +/- 0.7 U/g wet weight) were decreased (all p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Fifteen patients in whom various parts of the small intestine had been resected because of Crohn's disease or mesenteric thrombosis and 10 healthy volunteers were studied. A 50-g oral glucose load (OGTT) and an intravenous glucose infusion giving the same plasma glucose profile as the OGTT were carried out to study (a) the relation between the plasma gastric inhibitory polypeptide (GIP) levels after oral glucose and the length and nature of the intestinal residues and (b) the importance of endogenous GIP as an incretin in man. The magnitude of the increase in plasma GIP after oral glucose load was positively correlated to the length of residual jejunum. The incretin effect was positively correlated to the length of residual intestine. Patients with preserved ileal residues had larger incretin effects than patients with less than 150 cm jejunal residues and no ileal residues, although the integrated increases in plasma GIP after oral glucose were equal. Compared with healthy volunteers, the patients with more than 150 cm residual jejunum had significantly higher increases in plasma GIP and normal incretin effects. The GIP release and the incretin effect in patients with preserved ileal residues were normal. The incretin effect of the patients with less than 150 cm jejunum was significantly subnormal in spite of a normal GIP release. These findings indicate that the upper intestine releases GIP after oral glucose and that other as yet unknown intestinal hormonal factors act as incretins in concert with GIP.

A newborn infant with severe hypoglycaemia and nesidioblastosis was subjected to subtotal pancreatectomy without any sign of improvement. In spite of very low plasma levels of glucose (i.e. less than 1 mmol/l) plasma insulin concentrations were high (i.e. greater than 700 pmol/l). Plasma proinsulin was considerably enhanced comprising 43% of the total insulin immunoreactivity. Plasma glucagon concentrations were normal. Postoperatively normal to subnormal plasma glucose levels could only be maintained by treatment with frequent meals, diazoxide and intramuscular injections of a long-acting glucagon preparation. With time, signs of mental retardation became obvious.

Approximately 10-20% of patients admitted with acute gastrointestinal bleeding suffer from hemorrhagic erosive gastritis. A material of 36 patients is presented and the literature reviewed. The moderate bleeders stop bleeding within hours to a few days and the majority may safely be managed conservatively, i.e. with blood transfusions. The severe bleeders continue to bleed for a long time and surgery is often required. Different operative procedures have been suggested. The mortality in this group of patients is high--nearly 30%, and the frequency of postoperative rebleeding is also high. It is concluded that there is no absolute operative procedure of choice but vagotomy combined with subtotal gastrectomy offer the best protection against rebleeding. Treatment with selective application of vasoconstrictors is mentioned.