Histopathological changes of primary HIV infection. Description of three cases and review of the literature

The histopathological changes observed in the cutaneous rash of three patients who suffered the acute phase of HFV infection are described. In all three patients a perivascular and interstitial inflammatory infiltrate was present in the upper and mid-reticular dermis. In one biopsy isolated areas of epidermal necrosis were observed and in the two other biopsies a perifollicular inflammatory infiltrate was detected with perforation in one case. Furthermore, a periductal infiltrate was observed in one of these biopsies.     

Fat embolism syndrome following bone marrow harvesting

A case of fat embolism syndrome is reported following an uncomplicated bone marrow harvest. The presenting symptoms were restlessness, shortness of breath and arterial hypoxemia. A lung perfusion scan ruled out the presence of a lung thromboembolism. The patient received supportive therapy and recovered within a few hours. We speculate that the larger gauge needle (13 vs 15) used to aspirate the bone marrow may have represented increased trauma to the iliac crest leading to fat embolism.     

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.     

ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells.

PURPOSE: ZD1839 is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) that has shown clinical activity against EGFR-expressing tumors. Our aim was to explore the effects of ZD1839 in breast cancer cell lines expressing different levels of EGFR and the closely related HER2 receptor. EXPERIMENTAL DESIGN: We studied the growth-inhibitory effects of ZD1839 in a series of breast carcinoma cell lines. In HER2-overexpressing BT-474 breast cancer cells, we studied the effects of ZD1839 on cell growth and heterodimerization of receptors under basal and ligand-stimulated conditions. RESULTS: ZD1839 was an equally potent inhibitor of growth in breast cancer cells expressing high levels of EGFR and HER2. In BT-474 breast cancer cells, ZD1839 abolished EGF- and heregulin-induced activation of ErbB receptors and downstream signaling molecules. Because ZD1839 does not inhibit the HER2 tyrosine kinase in vitro, and because heregulin is a ligand that activates HER2 by binding to HER3 and HER4 but does not bind to the EGFR, our findings suggested that ZD1839 interfered with HER2 function in intact cells. Searching for mechanisms, we report that ZD1839 induces the formation of inactive unphosphorylated EGFR/HER2 and EGFR/HER3 heterodimers. Furthermore, ZD1839 completely abolishes basal and heregulin-induced formation of active phosphorylated HER2/HER3 heterodimers. CONCLUSIONS: ZD1839 inhibits the growth of HER2-overexpressing breast cancer cells, possibly by sequestration of HER2 and HER3 receptors in an inactive heterodimer configuration with the EGFR. Our findings suggest that there is a strong rationale to conduct clinical trials of ZD1839 in patients with HER2-overexpressing breast tumors.     

Feasibility trial of high-dose 7-day continuous-infusion ifosfamide given on an outpatient basis

 High-dose ifosfamide (HD-IFX) has shown significant antitumor activity in advanced sarcoma and breast carcinoma. The use of uroprotective agents and the availability of ambulatory continuous-infusion pumps has allowed dose escalation in the administration of ifosfamide (IFX) on an outpatient schedule. We report the results of a phase II trial of IFX given at high doses to heavily pretreated patients. IFX was infused at 2 g/m² per day for a total of 7 days through a central venous access, with cycles being repeated every 21 days. Mesna was given concomitantly at equimolar doses. No hematopoietic support was used. A total of 27 heavily pretreated patients whose disease had progressed during conventional-dose chemotherapy were included (14 sarcomas, 10 breast carcinomas, and 3 bladder carcinomas). Reversible neutropenia and gastrointestinal toxicity were the most frequently encountered toxicities. Only two patients developed transient renal failure, and two others developed central nervous system toxicity. No treatment-related death was observed. Of 22 patients who were evaluable for response, 6 (27%) showed an objective response (OR), all ORs being partial responses (PRs) with a median duration of 6 months, and 12 patients had stable disease (SD; 55%) with a median duration of 3.5 months. The median overall survival (OS) was 6 months. Three patients underwent high-dose chemotherapy after showing a response to our IFX schedule. We conclude that continuous-infusion IFX given in an outpatient setting is a feasible and active regimen that produces, a manageable toxicity profile in heavily pretreated breast cancer and sarcoma patients. Early institution of this schedule in less advanced stages could improve the results obtained. Received: 30 June 1996 / Accepted: 20 January 1997     

Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials.

PURPOSE: Most cases of non-small-cell lung cancer (NSCLC) with dramatic responses to gefitinib have specific activating mutations in the epidermal growth factor receptor (EGFR), but the predictive value of these mutations has not been defined in large clinical trials. The goal of this study was to determine the contribution of molecular alterations in EGFR to response and survival within the phase II (IDEAL) and phase III (INTACT) trials of gefitinib. PATIENTS AND METHODS: We analyzed the frequency of EGFR mutations in lung cancer specimens from both the IDEAL and INTACT trials and compared it with EGFR gene amplification, another genetic abnormality in NSCLC. RESULTS: EGFR mutations correlated with previously identified clinical features of gefitinib response, including adenocarcinoma histology, absence of smoking history, female sex, and Asian ethnicity. No such association was seen in patients whose tumors had EGFR amplification, suggesting that these molecular markers identify different biologic subsets of NSCLC. In the IDEAL trials, responses to gefitinib were seen in six of 13 tumors (46%) with an EGFR mutation, two of seven tumors (29%) with amplification, and five of 56 tumors (9%) with neither mutation nor amplification (P = .001 for either EGFR mutation or amplification v neither abnormality). Analysis of the INTACT trials did not show a statistically significant difference in response to gefitinib plus chemotherapy according to EGFR genotype. CONCLUSION: EGFR mutations and, to a lesser extent, amplification appear to identify distinct subsets of NSCLC with an increased response to gefitinib. The combination of gefitinib with chemotherapy does not improve survival in patients with these molecular markers.     

Pediatric Cutaneous Lupus Erythematosus Treated with Pulsed Dye Laser

Pulsed dye laser (PDL) has been used in adults to treat refractory cutaneous lupus erythematosus (CLE). We report the first case of CLE in a child successfully treated with PDL.