A phase 1 trial of recombinant human IL-21 in combination with cetuximab in patients with metastatic colorectal cancer.

BACKGROUND: Pre-clinical data indicate enhanced anti-tumour activity when combining recombinant human interleukin-21 (rIL-21), a class 1 cytokine, with cetuximab, a monoclonal antibody, targeting the epidermal growth factor receptor. This phase 1 trial assessed the safety and tolerability of escalating doses of rIL-21 in combination with cetuximab in chemo-naïve patients with stage IV colorectal cancer. PATIENTS AND METHODS: Sequential cohorts of PS 0-1, asymptomatic patients, were treated weekly with cetuximab 250 mg m(-2) intravenously (i.v.) plus escalating i.v. doses of rIL-21 following an initial loading dose of cetuximab 400 mg m(-2). Initial treatment period was 8 weeks, with extension permitted in patients without disease progression. RESULTS: In all, 15 patients were included in this study. Adverse events related to rIL-21 or rIL-21 plus cetuximab included lethargy, nausea/vomiting, stomatitis, lymphopenia and pyrexia and were mainly ≤ grade 2. One dose limiting toxicity occurred (grade 3 diarrhoea). Maximum tolerated dose was not determined because of the premature study closure. Maximum administered dose was 100 µg kg(-1) rIL-21 weekly. In all, 60% of the patients had stable disease. Immune activation was confirmed by various T- and NK-cell activation biomarkers, including dose-dependent increases in serum sCD25. CONCLUSION: rIL-21 weekly combined with cetuximab is well tolerated at doses up to 100 µg kg(-1) and results in activation of immune response biomarkers.

The role of mismatch repair in small-cell lung cancer cells.

The role of mismatch repair (MMR) in small-cell lung cancer (SCLC) is controversial, as the phenotype of a MMR-deficiency, microsatellite instability (MSI), has been reported to range from 0 to 76%. We studied the MMR pathway in a panel of 21 SCLC cell lines and observed a highly heterogeneous pattern of MMR gene expression. A significant correlation between the mRNA and protein levels was found. We demonstrate that low hMLH1 gene expression was not linked to promoter CpG methylation. One cell line (86MI) was found to be deficient in MMR and exhibited resistance to the alkylating agent MNNG. Surprisingly, MSI was not detected in 86MI and it appears to express all the major MMR components hMSH2, hMSH6, hMLH1, hPMS2, hMSH3, hMLH3, MBD4 (MED1) and hExo1. These data are consistent with at least two possibilities: (1) A missense mutation in one of the MMR genes, which dissociates MSI from drug resistance, or (2) inactivation of a second pathway that leads to MMR-deficiency and MNNG resistance, but induces negligible levels of MSI. We conclude that MMR deficiency is largely not associated with the pathogenesis of SCLC.

Antibacterial effect of protamine in combination with EDTA and refrigeration.

The antimicrobial effect of protamine (clupeine) on a range of gram-positive and gram-negative foodborne pathogens and spoilage bacteria, was evaluated using an agar dilution assay and a broth dilution assay with Alamar Blue as growth indicator. Protamine was tested alone at concentrations from 0 to 10,000 microg/ml, and in combination with EDTA (0.9 mM). Assays were performed at 5 degrees C, 10 degrees C, 18 degrees C and 30 degrees C to test the effect of temperature. Minimum inhibitory concentration (MIC) values ranged from 10 microg/ml for Brochothrix thermosphacta to no inhibition at 10,000 microg/ml for bacteria such as Aeromonas hydrophila, proteolytic strains of Clostridium botulinum, Hafnia alvei and Morganella morganii. The minimum bactericidal concentrations (MBCs) were generally higher than MICs. In combination with EDTA, MICs of protamine decreased for gram-negative test strains, whereas EDTA alone inhibited gram-positive strains. The effect of assay incubation temperature was variable and not clear for most strains. Concentrations of 100-750 microg/ml protamine inhibited the five non-proteolytic C. botulinum strains, while none of the eight proteolytic strains was inhibited, indicating the possible role of proteolytic enzymes in protecting cells from protamine. Clearing zones, indicative of proteolytic activity, were observed in the opaque TSB-agarose around colonies of some but not all protamine-resistant bacteria, suggesting that this is not the only resistance mechanism. Addition of 5% (w/v) gelatin to study the effect of an increased protein concentration in the agar dilution assay showed that electrostatic interactions between protamine and the protein decreased the antimicrobial efficacy of the peptide.

Solubility and antimicrobial efficacy of protamine on Listeria monocytogenes and Escherichia coli as influenced by pH.

The antimicrobial efficacy of protamine on Listeria monocytogenes and Escherichia coli was evaluated at concentrations from 50 to 10 000 microgram ml-1 and pH levels from 5.5 to 8.0. The minimum inhibitory concentrations decreased with increasing pH. Protamine inhibited E. coli at all pH values while L. monocytogenes was inhibited at pH 6.5 and above. The antimicrobial efficacy of protamine decreased in the presence of negatively charged gelatine B but remained almost unchanged with addition of the positively charged gelatine A. Binding studies showed that the amount of protamine adsorbed to culture media components in tryptic soy broth and bacterial cells increased with increasing pH values. The increased efficacy of protamine at alkaline pH may be explained on the basis of an increase in electrostatic affinity for the cell surface of target cells. E. coli produced a protamine-degrading enzyme, however, was still susceptible to protamine.

[Ectopic thyroid gland in the submandibular region]. / Ektopisk thyreoidea i submandibulaerlogen.

A case of an ectopic thyroid gland in the submandibular region is presented. The embryological aspects are discussed.

Polypoidal carcinosarcoma of the oropharynx: a clinicopathological and immunohistochemical study.

Polypoidal squamous cell carcinomas, with a sarcomatous stroma, in the upper aerodigestive tract are very rare but well described tumours. They are associated with a multifarious nomenclature because of different opinions regarding their histology and histogenesis. The main issue is whether the stroma component is a true sarcoma or a benign reactive lesion. In order to draw the attention of otolaryngologists and pathologists to the characteristic features of this rare tumour, two cases originating from the oropharynx are presented. Both tumours were pedunculated and polypoidal, and their bulk consisted of a bizarre sarcoma-like stroma covered with granulation tissue. In some areas of the surface, however, atypical squamous cell epithelium with foci of invasive carcinoma was found. In the vicinity of the latter both tumours contained areas of adenocarcinoma. After surgical excision followed by radiation therapy, there was no recurrence after two and five years, respectively. The histological and immunohistochemical findings support the assumption that these two tumours are carcinosarcomas. Adenocarcinomatous elements in this type of tumour have to our knowledge been reported only twice previously and have never been observed in the pharynx.

Pea fiber lowers fasting and postprandial blood triglyceride concentrations in humans.

The effect of a pea cell wall fiber preparation with a high content of soluble fiber on fasting and postprandial blood lipids was investigated in young healthy subjects. Inclusion of 33 g pea fiber product/10 MJ (20 g dietary fiber) in a low fiber diet was tested in five men and six women (mean age 23 y) in a strictly controlled randomized cross-over intervention study over 2 wk separated by a 2-wk period of habitual diet consumption. No significant differences in fasting concentrations of total cholesterol, LDL cholesterol or HDL cholesterol were observed, whereas total and VLDL triglyceride concentrations were lower when subjects consumed the pea fiber diet compared with the low fiber diet (P < 0.05). Postprandial response to pea fiber was studied in eight men. Addition of 12 g pea fiber product/ 10 MJ to a breakfast meal and 15 g/10 MJ to the following lunch meal resulted in significantly lower total triglyceride (P = 0.01), chylomicron triglyceride (P = 0.03) and insulin (P = 0.003) concentrations after the lunch meal compared with results following the same meal without pea fiber. No differences were observed in glycemic response. In conclusion, this source of dietary fiber lowered fasting and postprandial triglyceride concentrations but did not change fasting cholesterol concentrations.

[Foreign body in the esophagus]. / Corpus alienum esophagi.

A ten year retrospective survey of 346 cases of oesophageal foreign bodies is reported. Although coins were the most frequent foreign bodies in the pediatry group, meat was the most common offender in the material taken as a whole. Rigid oesophagoscopy in general anaesthesia was performed on 312 patients. A foreign body was removed in 281 cases (90%). Only one case of oesophageal cancer was discovered. The risk of iatrogenic perforation of the oesophagus was greatest in old patients who had a lump of meat stuck in the distal third of the oesophagus.

[CO2 laser treatment of proximal pharyngo-esophageal diverticula (Zenker's diverticula)]. / CO2-laser behandling af proksimale faryngo-øsofageale divertikler (Zenker's divertikel).

The pharyngo-esophageal diverticulum (Zenker's diverticulum) has traditionally been treated operatively by an external approach. Since the 1950's the endoscopic technique has been performed increasingly as a good alternative. Since 1989, we have treated Zenker's diverticulum endoscopically as a standard procedure, and hereby we present our results here. We use the Benjamin-Hollinger diverticuloscope, through which the septum between the diverticulum and esophagus is divided by a CO2-laser. Nine patients have been treated, five men and four women. Mean age 77 years (range 59-93). Diverticulum size varied between 1x2 cm and 6x6.5 cm. No major complications occurred. One patient had recurrence of symptoms after three months and was reoperated with the same technique. The mean observation period is 12 months (range 4-28). We find the endoscopic CO2-laser technique safe, and for the elderly age group suffering from Zenker's diverticulum, less traumatic than the external approach.