A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours.

BACKGROUND: We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor). METHODS: Patients with advanced solid tumours, refractory to standard therapy received selumetinib hydrogen sulphate capsules orally twice daily, and cixutumumab intravenously on days 1 and 15 of each 28-day cycle. The study used a 3+3 design, with a dose-finding cohort followed by an expansion cohort at the maximally tolerated dose that included pharmacokinetic and pharmacodynamic correlative studies. RESULTS: Thirty patients were enrolled, with 16 in the dose-finding cohort and 14 in the expansion cohort. Grade 3 or greater toxicities included nausea and vomiting, anaemia, CVA, hypertension, hyperglycaemia, and ophthalmic symptoms. The maximally tolerated combination dose was 50 mg twice daily of selumetinib and 12 mg kg(-1) every 2 weeks of cixutumumab. Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of >6 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma. Comparison of pre- and on-treatment biopsies showed significant suppression of pERK and pS6 activity with treatment. CONCLUSIONS: Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition.

Expression of Ki-67 and cytokeratin 20 in hyperplastic polyps of the colorectum.

AIMS: To study the expression of Ki-67 and cytokeratin 20 (CK20) in a group of hyperplastic polyps (including a group with "atypical" features) with the aim of determining whether upper crypt Ki-67 staining and lower crypt CK20 staining correlated with these atypical features, as assessed by light microscopy. METHODS: Fifty seven formalin fixed, paraffin wax embedded hyperplastic colorectal polyps from 53 patients were selected on histological grounds; these comprised 26 typical polyps and 31 with atypical features, which included nuclear hyperchromatism, basal crowding, and increased mitotic activity. These polyps were examined using a standard immunohistochemical method with antibodies against CK20 and Ki-67. Comparisons were made with normal mucosa, adenomatous polyps, and carcinomas. RESULTS: Of the 26 typical polyps, 17 showed the usual pattern of lower crypt Ki-67 and upper crypt CK20 staining; one with upper crypt Ki-67 staining but normal surface CK20 staining; seven with Ki-67 confined to the lower half of crypts but with scattered lower crypt CK20; and one with both upper crypt Ki-67 staining, together with scattered CK20 basal staining. Of the 31 polyps with atypical features, 11 showed the usual staining pattern of lower crypt Ki-67 staining and surface staining with CK20; two showed Ki-67 staining extending into the upper half of crypts, but with a normal surface staining with CK20; 14 showed Ki-67 confined to the lower half of crypts, but scattered lower crypt staining with CK20; and four showed upper crypt Ki-67 staining together with scattered CK20 lower crypt staining. CONCLUSIONS: The normal pattern of lower crypt Ki-67 and upper crypt CK20 was seen in 28 of the 57 hyperplastic polyps and, in general, this corresponded with standard light microscopic appearances. Twenty one of the 57 polyps showed lower crypt mosaic CK20 staining, which in general corresponded with basal abnormalities on light microscopy, although seven specimens had normal appearances. Two smaller subsets emerged, one showing upper crypt Ki-67 staining in the presence of normal CK20 expression (three cases) and another in which a combination of lower crypt CK20 and upper crypt Ki-67 expression was seen (five cases). This last pattern was similar to that of neoplastic polyps and raises the possibility that a subgroup of hyperplastic polyps exists that may be a variant with malignant potential. Further studies with markers of mismatch repair genes and K-ras mutations may help to clarify this issue.

Cyclooxygenase-2 expression in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence.

OBJECTIVE: Increased expression of the inducible cyclooxygenase 2 (COX-2) enzyme has been detected in esophageal and colonic adenocarcinoma, and intake of aspirin and non-steroidal anti-inflammatory drugs, known COX-2 inhibitors, have been associated with reduced tumor formation. Elevated COX-2 mRNA but variable protein expression has been demonstrated in Barrett's epithelium, and we have, therefore, sought to evaluate the expression of COX-2 protein throughout the Barrett's metaplasia-dysplasia-adenocarcinoma sequence. METHODS: Paraffin-embedded esophageal biopsies from 56 different patients with Barrett's esophagus were analyzed for COX-2 expression by immunohistochemistry. Twenty contained nondysplastic intestinal and gastric metaplasia, 12 demonstrated low-grade dysplasia (LGD), 12 high-grade dysplasia (HGD), and 12 contained invasive adenocarcinoma. RESULTS: Epithelial expression of COX-2 protein was detected in 75% (15/20) of benign cases, 83% (10/12) of cases with LGD, and 100% of cases with HGD or adenocarcinoma. Using a semiquantitative analysis, median staining scores for the groups were 2, 3, 14, and 13, respectively (scale 0-16), with the expression being significantly higher in the HGD and cancer groups compared to benign and LGD groups (p < 0.001). CONCLUSIONS: This study demonstrates clear COX-2 expression in the epithelial cells in Barrett's metaplasia, confirms elevated expression in adenocarcinoma, and shows that the elevation in expression occurs in the progression from LGD to HGD.

A randomized study to evaluate the effect of a perioperative infusion of dopexamine on colonic mucosal ischemia after aortic surgery.

PURPOSE: Colonic ischemia after aortic surgery is associated with increased mortality and morbidity rates. This study was conducted as a single-center side arm to a multicenter, randomized, placebo-controlled study to evaluate the effect of dopexamine hydrochloride on its incidence. METHODS: Thirty patients, mean age 65.1 years (range, 46-84), undergoing elective infrarenal aortic surgery were entered. Preoperative hemodynamic and respiratory parameters were optimized. Patients were then randomly assigned to receive a perioperative infusion of dopexamine at 2 microg/kg per minute (n = 12) or 0.9% saline placebo (n = 18). All patients underwent colonoscopy and biopsy preoperatively and 1 week postoperatively. Specimens were assessed for evidence of mucosal ischemia, presence of mast cell tryptase, myeloperoxidase activity, and both the inducible and endothelial isoforms of nitric oxide synthase. RESULTS: There was no significant difference in perioperative fluid and blood requirements or hemodynamic and respiratory parameters between the two groups. However, there was significantly less evidence of mucosal ischemic changes in dopexamine-treated patients (n = 1) compared with placebo (n = 8) (P =.049). Furthermore, when preoperative biopsies were compared with those performed 1 week postoperatively, nine (50%) patients in the placebo group and two (16.7%) in the dopexamine group scored worse. Although there was no significant difference in inflammatory markers between the two groups, both mast cell tryptase and myeloperoxidase expression were increased in patients with histologic evidence of ischemia (P <.05). Furthermore, inducible nitric oxide synthase staining within the vascular (P =.001) and lamina propria (P <.05) components of the mucosa was also significantly greater. CONCLUSION: A perioperative dopexamine infusion affords significant histologic protection to colonic mucosa after aortic surgery.

Dopexamine reduces the incidence of acute inflammation in the gut mucosa after abdominal surgery in high-risk patients.

OBJECTIVE: To evaluate the effect of dopexamine on the incidence of acute inflammation in the stomach/duodenum in patients undergoing abdominal surgery > or =1.5 hrs with a minimum of one high-risk criterion. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. This study was conducted as a side arm to a multicenter, multinational study. SETTING: University hospital in an adult intensive care unit. PATIENTS: Thirty-eight patients. INTERVENTIONS: Patients were stabilized with fluid, blood products, and supplementary oxygen to achieve predetermined goals: cardiac index > 2.5 L/min/m2, mean arterial blood pressure of 70 mm Hg, pulmonary arterial occlusion pressure of 10 mm Hg, hemoglobin of 100 g/L, and arterial saturation of 94%. After stabilization, the study drug (either placebo [group A], dopexamine 0.5 microg/kg/min [group B], or dopexamine 2.0 microg/kg/min [group C]) was commenced. The study drug infusion was started 2 to 12 hrs before surgery and infused for 24 hrs after surgery. Estimation of upper gut blood flow was assessed using a gastric tonometer, and gastroscopy with biopsy was performed before surgery (after induction of anesthesia) and 72 hrs after surgery. Comparisons were made between endoscopic findings and histologic proof of acute inflammatory changes. In addition, biopsies were assessed for the presence in the mucosa of mast cells, myeloperoxidase activity, and inducible nitric oxide synthase. MEASUREMENTS AND MAIN RESULTS: Intramucosal pH decreased significantly with time in all three groups (p < .001), reaching the lowest point at the end of surgery. There was no difference among the groups. Endoscopy visualized acute inflammatory changes in 58.3% of group A patients, 46.2% of group B patients, and 53.90% of group C patients after hemodynamic optimization. At 72 hrs, dopexamine-treated patients compared with placebo-treated patients had a significantly lower incidence of gastric and duodenal acute inflammatory changes, as defined by myeloperoxidase activity (37.5% in groups B and C vs. 86% in group A; p < .05). CONCLUSION: Dopexamine in doses of 0.5 and 2.0 microg/kg/min affords significant histologic protection to the upper gastrointestinal tract mucosa 72 hrs after operation in high-risk surgical patients undergoing abdominal surgery.

Vascular surgical society of great britain and ireland: randomized double-blind study of dopexamine versus placebo in aortic surgery

BACKGROUND: Mechanisms involved in the development of colon- ic ischaemia are not fully understood and there are conflicting reports regarding predisposing factors. The aim of this study was to evaluate the effect of dopexamine hydrochloride on the incidence of colonic ischaemia following aortic surgery and to correlate immunohistochemical markers of inflammatory activation in its pathogenesis. METHODS: Thirty patients, of mean age 65 (range 46-84) years, undergoing elective infrarenal aortic surgery were randomized to receive a perioperative infusion of either dopexamine 2 &mgr;g kg-1 min-1 (n = 12) or 0.9 per cent saline placebo (n = 18). All patients underwent colonoscopy and biopsy following induction of anaesthesia and at 1 week after operation. Sections were stained with haematoxylin and eosin, and for mast cell tryptase (MCT), myeloperoxidase (MPO) and both the inducible (iNOS) and endothelial (eNOS) isoforms of nitric oxide synthase. Sections were analysed blindly and independently by two histopathologists. Patient and operative data were collected and stored separately. RESULTS: Colonic ischaemia was noted in nine patients based on microscopic findings. Endoscopy alone had a sensitivity of 56 per cent. There was a significantly lower incidence of colonic ischaemia in patients receiving dopexamine compared with placebo (P < 0.05). One death resulted from colonic infarction in the placebo group 11 days after operation. There was increased MPO and MCT expression in patients with histological evidence of ischaemia (P < 0.05); iNOS staining within the vascular (P = 0.001) and lamina propria (P < 0.05) components of the mucosa was also significantly greater. No association was found with eNOS. CONCLUSION: Perioperative dopexamine infusion confers a degree of protection to colonic mucosa following aortic surgery, possibly through an anti-inflammatory effect.