Olfactory Neuroblastoma and Neuroendocrine Carcinoma of the Anterior Skull Base: Treatment Results at the M.D. Anderson Cancer Center

Updated information on the pathologic characterization and treatment of olfactory neurobiastoma (ON) and neuroendocrine carcinoma (NEC) diseases is presented. A series of patients with ON or NEC was evaluated and retrospectively staged using the UCLA system. The parameters evaluated were symptoms, age, sex, risk factor assessment, stage of disease, treatment, and clinical outcome. The median follow-up was 3 years (range, 18 months to 23 years). The predominant therapy (63%) for ON was combined surgery and radiotherapy. Surgery alone or in combination with ancillary treatment was used in 58% of patients with NEC. For the most receat years of the study, patients with NEC have been treated successfully with combined chemotherapy and radiotherapy. Seventy percent of the patients with ON and 75% of the patients with NEC were clinically free of disease during the defined follow-up period. Surgical therapy consisting of a craniofacial resection combined with postoperative radiotherapy has resulted in good local and long-term control of ON. Our experience indicates that combined chemoradiation is an appropriate therapeutic approach for NEC.     

Tonometry with a new non-contact tonometer

We conducted comparative measurements with 100 healthy probands and patients suffering of glaucoma with both a Goldmann Applanation Tonometer (GAT) and the new Keeler Non Contact Tonometer (NCT). A noticeable conformity of mean values in the group I with values under 23 mm Hg and in group II with values greater or equal 23 mm Hg was obvious. The results of three NCT measurement values were compared with those of four measurements. The Keeler NCT nearly fulfills the needed criteria for the first group with pressure under 23 mm Hg except for a high standard deviation. In group II (pressure greater or equal 23 mm Hg) the demanded nominal values are exceeded.     

Expression of CDX2 and MUC2 in Barrett's mucosa

Barrett's mucosa is a risk factor for esophageal adenocarcinoma and should be detected at an early stage. It is defined by the presence of columnar epithelium with goblet cells in the lower esophagus, but histologic diagnosis can be uncertain in the absence of distinct goblet cells. We investigated 55 biopsies from 48 patients with endoscopically plain Barrett's esophagus and performed immunohistochemistry for CDX2 and MUC2. In addition, alcian blue (pH 2,5)/PAS staining was done. In histologically unequivocal Barrett's mucosa, nuclear expression of CDX2 in goblet cells and many columnar cells, as well as cytoplasmic positivity for MUC2 in goblet cells, could be observed. Alcian blue (pH 2,5)/PAS stained acidic mucins in goblet cells and in some non-goblet columnar cells. In six cases, no definite Barrett's mucosa was present, and no expression of MUC2 could be observed. In these biopsies, there was granular cytoplasmic and/or focal nuclear staining for CDX2 in non-goblet columnar epithelial cells, indicating their intestinal differentiation. We suggest that this peculiar mucosa is the precursor of unequivocal Barrett's mucosa and would designate it early Barrett's mucosa. Alcian blue for acidic mucins is inconsistent in this epithelium and does not reliably indicate early intestinal differentiation.     

Adenoviral vectors expressing siRNAs for discovery and validation of gene function

RNA interference is a powerful tool for studying gene function and for drug target discovery in diverse organisms and cell types. In mammalian systems, small interfering RNAs (siRNAs), or DNA plasmids expressing these siRNAs, have been used to down-modulate gene expression. However, inefficient transfection protocols, in particular, for primary cell types, have hampered the use of these tools in disease-relevant cellular assays. To be able to use this technology for genome-wide function screening, a more robust transduction protocol, resulting in a longer duration of the knock-down effect, is required. Here, we describe the validation of adenoviral vectors that express hairpin RNAs that are further processed to siRNAs. Infection of cell lines, or primary human cells, with these viruses leads to an efficient, sequence-specific, and prolonged reduction of the corresponding target mRNA, resulting in a reduction of the encoded protein level in the cell. For knock-down of one of the targets, GalphaS, we have measured inhibition of ligand-dependent, G-protein-coupled signaling. It is expected that this technology will prove to be of great value in target validation and target discovery efforts.     

ZK 91296, a partial agonist at benzodiazepine receptors

ZK 91296 (ethyl 5-benzyloxy-4-methoxymethyl--carboline-3-carboxylate) is a potent and selective ligand for benzodiazepine (BZ) receptors. Biochemical investigations indicate that ZK 91296 may be a partial agonist at BZ receptors. Such partial agonism may explain to some extent why ZK 91296 needs higher BZ receptor occupancy than diazepam for the same effect against chemical convulsants and for behavioural effects. The lack of sedatiye effects, and the very potent inhibition of reflex epilepsy, spontaneous epilepsy and DMCM-induced seizures suggest, furthermore, that ZK 91296 may possess pharmacological selectivity for a particular type of BZ receptor interaction, perhaps including topographic as well as receptor subtype differentiation.     

WHO stufe II—Klinische Realität oder didaktisches Instrument?

INTRODUCTION: In 1986 the World Health Organisation (WHO) proposed an analgesic ladder for the effective therapy of cancer pain. The three standard analgesics making up this ladder are aspirin (non-opioid), codeine (weak opioid) and morphine (strong opioid). Adjuvant drugs may be added at any level. However, before 1986 step II analgesics (weak opioids) had never been tested in cancer pain relief. METHODS: This report presents a computer-assisted Medline (US National Library of Medicine) literature search restricted to the years 1986-1994, which was conducted to test the validity of the WHO guidelines, and in particular that of step II. RESULTS: We found seven retrospective studies and one prospective study on cancer pain treatment according to the proposed WHO guidelines that had been published since 1986. Every publication decribed the use of all three steps of the analgesic ladder. We found no prospective controlled trials demonstrating the efficacy and safety of WHO step II in particular. DISCUSSION: The use of the WHO guidelines "by mouth, by the clock and by the ladder" is now the mainstay of cancer pain management. Because of the guidelines' simplicity they found general acceptance and helped to establish an international pain therapy standard for worldwide use. Nevertheless, there is no scientific validation of WHO step II. In the absence of prospective controlled randomized trials additional longterm results are necessary. We need more data on the use of WHO step II and an update of the published guidelines taking account of modern sustained-release drugs. Up to now, step II of the WHO guidelines for cancer pain is not a clinical reality but at best a didactic instrument.