Background: From 2% to 10% of cancer patients treated with 5-fluorouracil (5-FU) will develop symptomatic cardiotoxicity. Nevertheless, the underlying pathophysiology is mostly unknown. Patients and ...methods We investigated the influence of intravenous chemotherapy (CTX) on the diameter of the brachial artery using high resolution ultrasound in patients with malignant tumors, mostly gastrointestinal cancer. Cytostatic drugs included 30 cases with 5-FU and 30 cases with non-5-FU CTX (cis/carboplatin, anthracycline and cyclophosphamide). In addition, plasma levels of big endothelin were assessed prior to and after CTX. Results: Fifteen of 30 patients (50%) showed a contraction of the brachial artery after the end of 5-FU application (median 11%, range 4.3–18.5), whereas no single contraction was noticed in 30 patients following non-5-FU-based CTX. Vessel tonus generally normalized within 30 min after stopping 5-FU. Five patients positive for 5-FU associated vessel contraction were repeatedly exposed to 5-FU. Vessel contractions reoccurred in 86% (18/21) of these administrations. When patients with 5-FU bolus application were pre-treated with glyceroltrinitrate no contraction of the brachial artery was detected in five out of five occasions. There was a trend towards increased big endothelin plasma levels after 5-FU application (median 1.52 versus 1.99 fmol/ml; P = 0.07), whereas big endothelin levels remained unchanged after non-5-FU CTX (1.83 versus 1.83 fmol/ml; P = 0.99). Conclusions: Application of 5-FU is commonly accompanied by arterial vessel contractions, which is likely to represent the first step in 5-FU-induced cardiotoxicity. 5-FU-associated vessel contractions were highly reproducible on re-exposure and were in the case of bolus application completely preventable by glyceroltrinitrate.
Due to limited acceptance of colonoscopy as diagnostic and screening test alternatives are warranted. Colon capsule endoscopy (CCE) has been shown to be a possible filter test, but because of ...logistical issues a second bowel preparation is usually required, if consecutive colonoscopy is needed. We therefore evaluated the feasibility of a single bowel preparation for both overnight CCE and (therapeutical) colonoscopy thereafter.
Patients from two university hospitals referred to undergo colonoscopy were prospectively included in a dual centre feasibility study. A polyethylene glycol (PEG) based bowel preparation-schedule with ingestion of a colon capsule endoscopy (CCE) at 10pm and subsequent colonoscopy at about 12am on the next day was investigated. The first generation PillCam colon capsule was used with 4 different preparation protocols containing several prokinetics in different compositions (i. e. metoclopramide, erythromycin, sennosoides). The main endpoint was the proportion of patients who completed both CCE and colonoscopy; secondary endpoints were capsule transit times, amount of colon seen on CCE, bowel cleanliness, sensitivity and specifity of CCE and patients' acceptance.
50 patients between 18 and 75 years were included. The sequence of overnight colon capsule endoscopy and colonoscopy was successfully completed in all but one (one refused colonoscopy). The capsule was excreted during recording time in 86 % of examinations, visualization of the complete colon was possible in 60 %, but adequate colon preparation was achieved in only 45 % irrespective of the regimen used. The preparation regimen consisting of a PEG-solution, erythromycin as prokinetic drug followed by PEG-solution as boost showed the largest proportion of adequate preparations. Overall sensitivity and specificity of CCE for polyps of any size were 65 % and 76 %, respectively. 26 of 30 patients (86.7 %) returned the subjective assessment questionnaire. 23 patients (88 %) reported mild to no discomfort or embarrassment during CCE, whereas 15 patients (58 %) did during the preparation procedure. Drinking the purgative solution was the most inconvenient step in 84 % of cases, drinking the boosts during CCE the second inconvenient step (60 %).
Overnight CCE-procedure followed by direct capsule-reading is feasible and safe and might avoid repetitive bowel preparation for subsequent colonoscopy. The bowel preparation needs to be improved.
The 60 day mortality is an established parameter for chemotherapy-related safety in randomised trials for metastatic colorectal cancer (mCRC). Prognostic factors associated with 60-day mortality ...would be helpful to identify high-risk patients in advance.
Individual baseline patient data from four randomised, controlled trials from the Arbeitsgemeinschaft Internistische Onkologie (AIO) study group were retrospectively analysed. Chemotherapy consisted of fluoropyrimidine (5-FU/capecitabine), irinotecan, oxaliplatin with or without bevacizumab or cetuximab. Prognostic factors were identified by univariate and multivariate logistic regression models in two cohorts: one limited to ECOG PS 0 and 1 and one including ECOG PS 2 patients.
A total of 1377 patients were evaluated. The analysis of ECOG PS 0, 1 and 2 patients consisted of 898 patients where a total of 33 deaths within the first 60 days of treatment (3.7%) occurred. In multivariate analysis, 60-day mortality was significantly associated with ECOG PS 2 and high leucocyte count (white blood cell, WBC). Odds ratio was 6.28 for WBC and 12.92 for ECOG PS 2. Exclusion of ECOG PS 2 patients but inclusion of one trial limited to ECOG PS 0 and 1 patients resulted in 1302 assessable patients and 44 early deaths (3.4%). In both cohorts, around 50% of deaths were disease related. WBC was confirmed as a significant risk factor for early death (OR 7.60). A combined score using ECOG PS 2 and WBC ≥8.000/µl is able to identify high-risk patients with a sensitivity of 18% and specificity of 98%.
In this large retrospective analysis of individual patient data, around 50% of early deaths were disease related. Elevated WBC was found strongly associated with increased 60-day mortality in first-line treatment of mCRC. The proposed AIO-60-Day-Mortality score serves as an additional trial exclusion criterion.
As previously shown, antibody treatment increased survival of patients with resected colorectal cancer of stage Dukes' C. Since the 5-year analysis was criticized because of the wide range (2.7 to ...7.5 years) of follow-up time, we performed a 7-year analysis with only four of 189 patients monitored for less than 5 years.
A total of 189 patients with resected Dukes' C colorectal cancer were randomly allocated to infusions of a total of 900 mg 17-1A antibody, 500 mg postoperatively followed by 4 monthly doses of 100 mg (n=99), or to observation only (n=90). Primary end points were overall survival and disease-free interval. Patients were stratified by a dynamic randomization according to center, sex, location of tumor, number of affected lymph nodes, and preoperative carcinoembryonic antigen concentration.
Randomization produced balanced distribution of risk factors. After 7 years of follow-up evaluation, treatment had reduced overall mortality by 32% (Cox's proportional hazard, P < .01; log-rank, P=.01) and decreased the recurrence rate by 23% (Cox's proportional hazard, P < .04; log-rank, P=.07). The intention-to-treat analysis gave a significant effect for overall survival (Cox's proportional hazard, P < .01; log-rank, P=.02) and disease-free survival (Cox's proportional hazard, P=.02; log-rank, P=.11 ). While distant metastases were significantly reduced (Cox's proportional hazard, P=.004; log-rank, P=.004), local relapses were not (Cox's proportional hazard, P=.65; log-rank, P=.52). This differential effect of 17-1A antibody on disseminated isolated tumor cells versus occult local satellites may explain the increased significance seen in the overall survival.
The now-matured study shows that 17-1A antibody administered after surgery prevents the development of distant metastasis in approximately one third of patients. The therapeutic effect is maintained after 7 years of follow-up evaluation.
Aims Sulfonylureas may interfere with ‘ischaemic preconditioning’ and worsen the prognosis in diabetic patients with acute myocardial infarction. Methods and Results Three hundred and fifty-seven ...non-diabetic patients admitted with acute myocardial infarction to one hospital over 6·5 years (72 deaths, in-hospital mortality 20·2%) were compared to 245 Type 2 diabetic patients categorized as having taken sulfonylureas (glibenclamide 7±3mg.day−1; n=76, 25 deaths=32·9%;P=0·025), not having taken sulfonylureas (n=89, 29 deaths=33·0%;P=0·012), and newly diagnosed as having diabetes (n=80, 20 deaths=25·0%). Survival was significantly different (log-rank test: P=0·03). Increments in creatine kinase and creatine kinaseMBactivity were higher in non-diabetic patients (P<0·01). Conclusions In-hospital mortality in Type 2 diabetic patients is higher than in non-diabetic patients suffering acute myocardial infarction regardless of whether or not they had been treated with sulfonylureas. Glibenclamide does not enlarge myocardial necroses.
The aim of this study was to evaluate the prognostic value of MSI-H and p53 overexpression in metastatic colorectal cancer (mCRC) treated with oxaliplatin and fluoropyrimidine-based first line ...chemotherapy.
Tumour samples were retrospectively obtained from 229 patients from a prospective randomised phase III trial of the AIO colorectal study group, comparing CAPOX and FUFOX in mCRC. Immunohistochemistry of p53 and MMR proteins as well as microsatellite analysis were performed.
The incidence of MSI-H and p53 overexpression was 7.9 % and 65.4 %, respectively. MSI-H status was not correlated with ORR, PFS and OS. We observed a trend to lower DCR for MSI-H tumours (65 % vs. 85 %, p = 0.055). p53 overexpression was not correlated with DCR, ORR and PFS. The median OS of patients with tumors with p53 overexpression was significantly longer compared to tumors withhout p53 overexpression (19.6 vs. 15.8 months; p = 0.05). The post-progression survival (PPS) of p53-positive patients undergoing 2nd and/or 3rd line chemotherapy with irinotecan and/or cetuximab was significantly longer compared to p53-negative patients.
MSI-H tumours tend to have lower disease control rates when treated with an oxaliplatin/fluoropyrmidin combination. mCRC patients with p53 overexpression undergoing an irinotecan containing second- or third-line chemotherapy after oxaliplatin failure have a significantly longer post-progression survival compared to patients without p53 overexpression. To validate the clinical impact of p53 in patients with mCRC treated with irinotecan- and/or cetuximab further studies are needed.
Reduced Insulinotropic Effect of Gastric Inhibitory Polypeptide in First-Degree Relatives of Patients With Type 2 Diabetes
Juris J. Meier 1 2 ,
Katrin Hücking 1 2 ,
Jens J. Holst 3 ,
Carolyn F. ...Deacon 3 ,
Wolff H. Schmiegel 1 and
Michael A. Nauck 1 2 4
1 Medizinische Klinik, Ruhr-Universität Bochum, Knappschafts-Krankenhaus, Bochum (Langendreer), Germany
2 Medizinische Klinik 1, Ruhr-Universität Bochum, St. Josef-Hospital, Bochum, Germany
3 Department of Medical Physiology, Panum Institute, University of Copenhagen, Copenhagen, Denmark
4 Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany
Abstract
In patients with type 2 diabetes, gastric inhibitory polypeptide (GIP) has lost much of its insulinotropic activity. Whether
this is similar in first-degree relatives of patients with type 2 diabetes is unknown. A total of 21 first-degree relatives,
10 patients with type 2 diabetes, and 10 control subjects (normal oral glucose tolerance) were examined. During a hyperglycemic
“clamp” (140 mg/dl for 120 min), synthetic human GIP (2 pmol · kg −1 · min −1 ) was infused intravenously (30–90 min). With exogenous GIP, patients with type 2 diabetes responded with a lower increment
(Δ) in insulin ( P = 0.0003) and C-peptide concentrations ( P < 0.0001) than control subjects. The GIP effects in first-degree relatives were diminished compared with control subjects
(Δ insulin: P = 0.04; Δ C-peptide: P = 0.016) but significantly higher than in patients with type 2 diabetes ( P ≤ 0.05). The responses over the time course were below the 95% CI derived from control subjects in 7 (insulin) and 11 (C-peptide)
of 21 first-degree relatives of patients with type 2 diabetes. In conclusion, a reduced insulinotropic activity of GIP is
typical for a substantial subgroup of normoglycemic first-degree relatives of patients with type 2 diabetes, pointing to an
early, possibly genetic defect.
Footnotes
Address correspondence and reprint requests to Prof. Dr. Michael Nauck, Diabeteszentrum Bad Lauterberg, Kirchberg 21, D-37431
Bad Lauterberg im Harz, Germany. E-mail: m.nauck{at}diabeteszentrum.de .
Received for publication 1 November 2000 and accepted in revised form 31 July 2001.
J.J.M. and K.H. contributed equally to this study.
ANOVA, analysis of variance; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide 1; HOMA, homeostasis model
assessment.
Abstract Background and scope The management of GOJ cancers remains controversial and may vary between countries. Evidence-based attitudes and guidelines are not easy to elaborate since most of the ...trials and studies reported mixed cases of oesophageal (both adenocarcinoma and squamous cell tumours), GOJ and gastric cancers. The aim of this expert discussion and position paper is to elaborate practical recommendations that integrate evidence-reported literature and experience-based attitude covering all clinical aspects of GOJ cancer across different specialities and countries in Europe. Methodology Opinion leaders, selected on scientific merit were asked to answer to a prepared set of questions covering the approach of GOJ tumours from definition to therapeutic strategies. All answers were then discussed during a plenary session and reported here in providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine. Results Definition, classification, diagnosis and staging of GOJ tumours were updated and debated. Therapeutic aspects including endoscopic therapy, surgical management, both multimodal curative and palliative management were also reviewed for proposing practical and consensual positions and recommendations whenever possible. Conclusion GOJ tumours deserve specific attention,not only for uniformising clinical management across countries but also for performing specific clinical and translational research,mainly in the curative perioperative setting.
PDF
