Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor.

PURPOSE: To investigate the safety and tolerability and to explore the pharmacokinetic and pharmacodynamic profile of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with solid tumors that express epidermal growth factor receptor (EGFR). PATIENTS AND METHODS: This was a phase I dose-escalation trial of EMD72000 in patients with advanced, EGFR-positive, solid malignancies that were not amenable to any established chemotherapy or radiotherapy treatment. EMD72000 was administered weekly without routine premedication until disease progression or unacceptable toxicity. RESULTS: Twenty-two patients were treated with EMD72000 at five different dose levels (400 to 2,000 mg/wk). National Cancer Institute common toxicity criteria grade 3 headache and fever occurring after the first infusion were dose limiting at 2,000 mg/wk; thus, the maximum-tolerated dose was 1,600 mg/wk. No other severe side effects, especially no allergic reactions or diarrhea, were observed. Acneiform skin reaction was the most common toxicity, but it was mild, with grade 1 in 11 patients (50%) and grade 2 in three patients (14%). Pharmacokinetic analyses demonstrated a predictable pharmacokinetic profile for EMD72000. Pharmacodynamic studies on serial skin biopsies revealed that EMD72000 effectively abrogated EGFR-mediated cell signaling (eg, reduced phosphorylation of EGFR and mitogen-activated protein kinase), with no alteration in total EGFR protein. Objective responses (23%; 95% CI, 8% to 45%) and disease stabilization (27%; 95% CI, 11% to 50%) were achieved at all dose levels, and responding patients received treatment for up to 18 months without cumulative toxicity. CONCLUSION: Treatment with EMD72000 was well tolerated and showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors. EMD72000 at the investigated doses significantly inhibited downstream EGFR-dependent processes.     

Effects of whole body hyperthermia (41.8 degrees C) on the frequency of tumor cells in the peripheral blood of patients with advanced malignancies.

PURPOSE: Combining heat with antineoplastic drugs has produced evidence of antitumor synergism. An increasing number of trials are investigating whole body hyperthermia (WBH) in combination with chemotherapy in patients with advanced malignancies. Here we investigated whether the hyperdynamic state of the circulation as a consequence of WBH may stimulate dissemination of malignant cells. EXPERIMENTAL DESIGN: WBH in combination with chemotherapy was administered by a radiant heat device to 20 consecutive patients with advanced epithelial malignancies. One WBH session lasted for approximately 4 h (90 min heating time, 60 min plateau at 41.8 degrees C, and 60-80 min cooling). Peripheral blood was drawn before WBH treatment (baseline), at the end of the plateau (1 h), and 24 h and 48 h thereafter. After removal of leukocytes using anti-CD45 magnetic beads, circulating tumor cells were detected immunocytochemically using the monoclonal antibody A45-B/B3, which binds to a common epitope present on various cytokeratins. RESULTS: The method used to detect tumor cells in the peripheral blood proved to be specific and very sensitive (detection limit 1 tumor cell per 1.7 x 10(5) peripheral blood mononuclear cell). Before WBH, 6 of 20 patients had cyto-keratin-positive cells in their blood. A treatment-induced increase in the number of circulating tumor cells became statistically significant at 24 h after WBH (P = 0.043) and was detected in a total of 9 patients, 5 of whom had no detectable malignant cells at baseline. There was no evidence of a correlation between an increase in the number of circulating tumor cells and increased metastasis frequency. CONCLUSIONS: Our findings suggest that WBH might induce a temporary release of tumor cells into the circulation, but this spread appears to be clinically not significant in patients with advanced malignancies.     

Detection and clinical implications of early systemic tumor cell dissemination in breast cancer.

Blood-borne distant metastasis is the leading cause of cancer-related death in breast cancer. The onset of this fundamental process can now be assessed in cancer patients using ultrasensitive immunocytochemical and molecular assays able to detect even single metastatic cells. Analyses of bone marrow (BM) samples show that disseminated cells are present in 20-40% of primary breast cancer patients without any clinical or histopathological signs of metastasis. The common homing of circulating breast cancer cells in BM is indicative for systemic tumor cell spread and predictive for growth of overt metastases in relevant organ sites such as bone, lung, or liver. Recent clinical studies involving more than 3000 breast cancer patients demonstrated that the presence of tumor cells in BM at primary diagnosis is an independent prognostic factor for unfavorable clinical outcome. To date, sampling of BM, however, is not a routine procedure in clinical management of breast cancer patients. Therefore, several research groups have developed sensitive assays for detection of circulating tumor cells in peripheral blood. Studies evaluating the clinical relevance of these blood assays are ongoing. Here, we will review the existing tumor cell assays and discuss their current clinical relevance and perspectives for the clinical management of breast cancer patients.     

Operative Behandlung von geburtstraumatischen Läsionen des Plexus brachialis

Zusammenfassung Fragestellung: Geburtstraumatische L?sionen des Plexus brachialis treten in 0,6–2,5‰ aller Geburten auf. 80–95% dieser L?sionen bilden sich spontan zurück. Sollte keine spontane Funktionsrückkehr innerhalb der ersten 6 Monate eintreten, mü?te nach entsprechender Diagnostik, wie elektrophysiologische und myelocomputertomographische Untersuchungen eine operative Freilegung des Plexus brachialis erfolgen. Methode: In einem Zeitraum von 5 Jahren haben wir 7 Kinder mit postpartaler Plexusl?sion unter 99 operativ versorgten Plexusl?sionen behandelt. 6/7 Kindern zeigten pr?operativ Wurzelausrisse. Bei 2 Kindern wurde eine Neurotisation, bei 4 eine autologe Transplantation und beim letzten eine ?u?ere Neurolyse des Plexus brachialis vorgenommen. Ergebnisse: Bisher wurden nur 3/7 Kindern über einen l?ngeren Zeitraum (26–42 Monate) nachuntersucht. Alle transplantierten Nerven zeigten klinisch eine Reinnervation. Eine Wiederherstellung der normalen Funktion war durch begleitende Wurzelausrisse limitiert. Schlu?folgerungen: Wir empfehlen als optimalen Zeitpunkt für die Operation den Zeitraum zwischen dem 6. und 9. Monat. Um optimale Ergebnisse bei diesen Kindern zu erzielen, mu? sich zun?chst eine intensive krankengymnastische Behandlung anschlie?en und sp?ter sollte die Option für Muskeltransfers und orthop?dische Operationen gew?hrleistet sein.      

Comparing sulindac with indomethacin for closure of ductus arteriosus in preterm infants

Objectives: A prospective study comparing the efficiacy and side-effects of oral sulindac with intravenous indomethacin in clinically stable preterm infants (<1750 g) requiring non-invasive closure of haemodynamically significant patent ductus arteriosus.
Methodology: As maturity and birthweight are the two major determinants of ductal closure, infants were matched as closely as possible for these parameters. An eligible patient was first assigned to the sulindac group and a subsequent patient with similar gestational age (± 1 week) and birthweight (±100 g) to the previously recruited infant would automatically receive indomethacin. A total of eight infants were enrolled in each group.
Results: The ductus arteriosus was successfully closed in all eight infants receiving indomethacin, and in seven of eight infants receiving sulindac. No significant differences were found with regards to the ductal size between the two groups at diagnosis or on each of the consecutive days of treatment ( P >0.25). More renal adverse effects were encountered in the indomethacin group. Significant differences in changes from baseline value for urine output, plasma sodium, urea and creatinine concentrations were noted at 24, 48 and 72 h after commencement of treatment between the two groups ( P <0.05). All the parameters returned to normal or pre-treatment levels 48 h after stopping therapy. Unexpectedly, severe gastrointestinal complications were encountered in the sulindac group.
Conclusions: Sulindac is capable of promoting ductal constriction in clinically stable preterm infants without compromising the renal function. The spectrum of gastrointestinal complications observed in sulindac treated infants were similar to those described for indomethacin. The use of sulindac for ductal closure in the preterm infant should remain experimental.     

The expression of transforming growth factor-beta1 (TGF-beta1) in hippocampal neurons: a temporary upregulated protein level after transient forebrain ischemia in the rat

Exogenous TGF-beta1 has been shown to protect neurons from damage induced in vitro and in vivo. In this study we attempted to examine the expression of endogenous TGF-beta1 mRNA and protein in the hippocampus of non-ischemic and ischemic rats, and to localize TGF-beta1 protein and DNA fragmentation by double-staining. Transient ischemia was induced for 10 min in Wistar rats by clamping both common carotid arteries and lowering blood pressure to 40 mmHg. Bioactive TGF-beta1 was selectively determined in CA1 pyramidal neurons of non-ischemic rats. It was upregulated after 3 h and 6 h of reperfusion corresponding to the increase in TGF-beta1 mRNA level detected by RT-PCR. Lectin and GFAP staining showed no detectable activated microglial cells and astrocytes in the hippocampus 3 h and 6 h after ischemia. When neuronal damage proceeded through day 2 to day 4 after ischemia as demonstrated by TUNEL-staining, TGF-beta1 immunoreactivity (ir) disappeared in damaged neurons but persisted in viable neurons although TGF-beta1 mRNA levels continuously increased. Double-staining revealed that TUNEL-positive neurons did not express TGF-beta1, while TUNEL-negative neurons in the CA1 subfield exhibited a distinct TGF-beta1 ir. These data indicate that hippocampal CA1 neurons can express TGF-beta1 under physiological conditions and upregulate its expression during the first hours after ischemia, that is independent of the activation of glial cells. The endogenous TGF-beta1 expressed in neurons may play a role in the pathological process of DNA degradation and delayed neuronal death after transient forebrain ischemia.