Evaluation of biologic end points and pharmacokinetics in patients with metastatic breast cancer after treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor.

PURPOSE: To evaluate changes in epidermal growth factor receptor (EGFR) phosphorylation and its downstream signaling in tumor and surrogate tissue biopsies in patients with metastatic breast cancer treated with erlotinib, an EGFR tyrosine kinase inhibitor, and to assess relationships between biomarkers in tumor and normal tissues and between biomarkers and pharmacokinetics. PATIENTS AND METHODS: Eighteen patients were treated orally with 150 mg/d of erlotinib. Ki67, EGFR, phosphorylated EGFR (pEGFR), phosphorylated mitogen-activated protein kinase (pMAPK), and phosphorylated AKT (pAKT) in 15 paired tumor, skin, and buccal mucosa biopsies (at baseline and after 1 month of therapy) were examined by immunohistochemistry and analyzed quantitatively. Pharmacokinetic sampling was also obtained. RESULTS: The stratum corneum layer and Ki67 in keratinocytes of the epidermis in 15 paired skin biopsies significantly decreased after treatment (P = .0005 and P = .0003, respectively). No significant change in Ki67 was detected in 15 tumors, and no responses were observed. One was EGFR-positive and displayed heterogeneous expression of the receptor, and 14 were EGFR-negative. In the EGFR-positive tumor, pEGFR, pMAPK, and pAKT were reduced after treatment. Paradoxically, pEGFR was increased in EGFR-negative tumors post-treatment (P = .001). Although markers were reduced in surrogate and tumor tissues in the patient with EGFR-positive tumor, no apparent associations were observed in patients with EGFR-negative tumor. CONCLUSION: Erlotinib has inhibitory biologic effects on normal surrogate tissues and on an EGFR-positive tumor. The lack of reduced tumor proliferation may be attributed to the heterogeneous expression of receptor in the EGFR-positive patient and absence of target in this cohort of heavily pretreated patients.     

Clinical application of NMP22 and urinary cytology in patients with hematuria or a history of urothelial carcinoma

For evaluation of the clinical application of immunoassay for nuclear matrix protein 22 (NMP22 immunoassay) and urinary cytology for early diagnosis and detection of bladder cancer in patients with hematuria and/or a previous history of bladder cancer, 209 urine samples obtained from 137 patients presenting episodes of hematuria or a history of bladder cancer were assayed for NMP22 levels and/or prepared for cytology examination. Biopsy was performed when any visible tumor was identified during cystoscopy examination. The median NMP22 concentrations measured in samples taken from patients with active bladder cancer, from patients with a history of bladder cancer but no active disease, from patients with hematuria, and from healthy volunteers were 18.95, 5.45, 6.39, and 3.75 U/ml, respectively. The urinary NMP22 level recorded for patients with urothelial carcinoma was significantly higher than that noted for individuals without active disease. The sensitivity of the NMP22 assay and of urinary cytology in diagnosing bladder cancer was 69% and 67%, respectively. In contrast, the specificity of these two diagnostic modalities reached 72% and 93%, respectively. The NMP22 assay is slightly more sensitive but less specific than urinary cytology in detecting bladder cancer. This study indicates that determination of urinary NMP22 levels is a useful and noninvasive tool for the detection of bladder cancer because of its high sensitivity. The urinary NMP22 assay may be used as a first-line routine screening method; however, it cannot replace the use of urinary cytology because of its lower specificity.     

A Cost-Effective and Rational Surgical Approach to Patients With Snoring,Upper Airway Resistance Syndrome,or Obstructive Sleep Apnea Syndrome

The past decade has seen several innovations in the surgical techniques available for treatment of patients with sleep-disordered breathing. Outpatient techniques such as laser-assisted uvulopalatoplasty (LAUP) and more aggressive procedures designed to address hypopharyngeal and base of tongue obstruction (genioglossus advancement and hyoid myotomy) have been developed and proven successful. We describe the efficacy of LAUP for snoring (72.7%), upper airway resistance syndrome (81.8%), and mild (mean[±SD] respiratory disturbance index [RDI] = 12 ± 8.1) obstructive sleep apnea (41.7%) in 56 patients who underwent 132 LAUP procedures in a 26-month period. Thirty-two patients with more significant obstructive sleep apnea (mean RDI = 41.8 ± 23.1) underwent multilevel pharyngeal surgery consisting of genioglossus advancement and hyoid myotomy combined with uvulopalatopharyngoplasty. The surgical success rate in this group of patients was 85.7% when commonly accepted criteria were applied. We recommend a stratified surgical approach to patients with sleep-disordered breathing. Progressively worse airway obstruction marked by multilevel pharyngeal collapse and more severe sleep-disordered breathing is treated with incrementally more aggressive surgery addressing multiple areas of the upper airway.     

International spread of major clones of methicillin resistant staphylococcus aureus: nosocomial endemicity of multi locus sequence type 239 in Saudi Arabia and Romania

Phenotypically identified methicillin resistant Staphylococcus aureus (MRSA) strains from several hospitals in Romania and Saudi Arabia (n = 103 and 68, respectively) were confirmed to be MRSA by mecA PCR and PBP-2' based latex agglutination. Subsequently, strains were differentiated at the sub-species level using pulsed field gel electrophoresis (PFGE) of SmaI DNA macro-restriction fragments. Comparison of the PFGE fingerprints identified major clusters of strains, persistently present in the various hospitals. Endemicity of certain strains was identified, amongst others one due to a particularly methicillin resistant type in the burn wound sector of the Romanian hospital. No PFGE-based overlap was found between the Saudi and Romanian strains. However, multi locus sequence typing (MLST), performed for 20% of all strains, revealed that genuine genetic similarity was obscured by the PFGE analysis. In both the Romanian and Saudi hospitals the renowned sequence type (ST) 239 was very over-represented. This was especially apparent in Saudi Arabia, where all strains except two shared the ST 239 genotype. This clonal type has previously been identified in a variety of other countries. Despite the MLST concordance, PFGE data indicate that ST 239 diversifies while maintaining its core genome intact. ST 80, another previously but less frequently identified clone, was introduced in 2000 in the Romanian institutes and persisted over the past 3 years as a frequent cause of infections in a surgical department. The successful MRSA types can acquire prominent positions in hospitals of previously low-endemicity MRSA status.     

Identification of a novel pulmonary oedema producing toxin from Indian red scorpion (Mesobuthus tamulus) venom.

The experiments were conducted to identify the toxin that produces pulmonary oedema in Mesobuthus tamulus (BT) envenomed animals. Crude BT venom was subjected to Sephadex gel filtration (G-75) and the fractions were screened for optical density (OD), neurotoxicity (prolongation of compound action potential in frog sciatic nerve) and lethality. All these parameters exhibited a peak between 54-94 ml eluates. Fractions of this peak were pooled (SP) and loaded on to carboxymethyl cellulose column. The column was then eluted with increasing buffer concentrations at constant pH and temperature. Eluates were screened for neurotoxicity and OD. Four peaks of neurotoxic activity (T1-T4) were detected. T2 and T3 were lethal whereas T1 and T4 were non-lethal. T2 exhibited mainly neurotoxicity and failed to augment phenyldiguanide (PDG)-induced reflex response or to produce pulmonary oedema. T3 was having minimal neurotoxic actions but augmented PDG-reflex and produced pulmonary oedema. The effects of T3 persisted even after dialysis with 8 kDa cut-off filter but not those of T2. The T3 effects resembled toxic manifestations of BT venom and were blocked by aprotinin pre-treatment. T3 demonstrated a band at approximately 100 kDa in SDS-PAGE. The results demonstrate the presence of a lethal, high molecular weight, pulmonary oedema producing toxin in BT venom.