Small-molecule inhibitors of the human epidermal receptor family.

Background: Small molecule inhibitors of human epidermal receptors (HER) have become an integral part of the armamentarium available to the medical oncologist in the treatment of solid tumor malignancies. At present, there are two small-molecule inhibitors (erlotinib and lapatinib) approved by the FDA in the USA, and a third inhibitor, gefitinib, is approved in other countries.

Objective: To summarize the current standards of care for these new agents in solid tumors, and to discuss ongoing clinical trials; to review the known mechanisms of action of these inhibitors as well as to discuss both the known predictive markers for response and likely mechanisms of resistance.

Correction of frontonasoethmoidal encephalocele: the HULA procedure.

Background: The frontonasoethmoidal encephalomeningocele deformity involves central herniation of a glial mass that "pushes outward" and deforms the medial orbit, medial canthus, nasomaxillary process, and nasal structures without resulting in hypertelorbitism. The authors studied a modification of the "Chula" repair, called the HULA procedure (H = hard-tissue sealant, U = undermine and excise encephalocele, L = lower supraorbital bar, A = augment nasal dorsum), which provided complete correction of the midline hard and soft-tissue structures using an intracranial and extracranial approach.

Methods: Filipino patients with frontonasoethmoidal encephalomeningoceles were treated by a civilian/military humanitarian team at Tripler Army Hospital (n = 12).

Intractable hyperemesis gravidarum, transient hyperthyroidism and intrauterine growth restriction associated with hyperreactio luteinalis. A case report.

Background: Hyperreactio luteinalis represents benign pregnancy-associated ovarian enlargement caused by multiple theca-lutein cysts. It is usually discovered incidentally at the time of ultrasound, cesarean section or postpartum tubal ligation with the majority of cases asymptomatic.

Case: A 30-year-old, nulliparous, West African woman initially presented with hyperemesis gravidarum at 8 weeks' gestation.

Multiple myeloma: evolving genetic events and host interactions.

Multiple myeloma is a neoplasm of terminally differentiated B cells (plasma cells) in which chromosome translocations frequently place oncogenes under the control of immunoglobulin enhancers. Unlike most haematopoietic cancers, multiple myeloma often has complex chromosomal abnormalities that are reminiscent of epithelial tumours. What causes full-blown myeloma? And can our molecular understanding of this common haematological malignancy be used to develop effective preventive and treatment strategies?

Identification and proposed mechanism of action of thymidine kinase inhibition associated with cellular exposure to camptothecin analogs.

Purpose: To investigate the effects of several camptothecin analogs including 9-aminocamptothecin (9-AC), SN38, topotecan, and irinotecan (CPT-11) on the enzymes involved in the pyrimidine salvage pathway including thymidylate synthase (TS). A COMPARE analysis using the NCI 60 cell line drug-screening panel suggested that there were similarities in the mechanisms of action of camptothecin analogs and TS inhibitors.

Methods: TS enzymatic activity was measured by both an in situ tritium release assay using both the H630 colon cancer cell line and the CEM human leukemia cell line, and by a radiolabelled in vitro assay using partially purified human TS as the enzyme source.

cbl-3: a new mammalian cbl family protein.

We have cloned a new human gene, cbl-3, which encodes a protein with marked homology to the cbl family of proteins. The predicted protein encoded by this gene retains the conserved phosphotyrosine binding domain (PTB) in the N-terminal and the zinc finger but is significantly shorter (MW 52.5 kDa) than the other mammalian cbl proteins.

cbl-b inhibits epidermal growth factor receptor signaling.

The role of cbl-b in signaling by the epidermal growth factor receptor (EGFR) was studied and compared with c-cbl. We demonstrate in vivo, that cbl-b, like c-cbl, is phosphorylated and recruited to the EGFR upon EGF stimulation and both cbl proteins can bind to the Grb2 adaptor protein. To investigate the functional role of cbl proteins in EGFR signaling, we transfected cbl-b or c-cbl into 32D cells overexpressing the EGFR (32D/EGFR).

Pulmonary edema and hyponatremia during hysteroscopic resection of uterine fibroids: case report.

Hyponatremia and fluid overload--the so-called TURP Syndrome--is a rare but well-understood complication of endoscopic resection of the prostate caused by rapid absorption of irrigating fluids from venous sinuses opened during the surgery. A similar syndrome occurring during endoscopic resection of the uterine mucosa has been postulated but only rarely described. New equipment and surgical techniques have recently been developed that allow for more invasive and extensive hysteroscopic surgery, which will inevitably lead to an increased incidence of this complication.

An overview of topoisomerase I-targeting agents.

The camptothecins are a new class of antitumor agents that target topoisomerase I. Irinotecan and topotecan are the most widely used camptothecin analogs in clinical practice, with documented clinical activity in colorectal and ovarian cancer. Ongoing clinical trials with these agents are further characterizing their spectra of clinical activity and determining their optimal schedule of administration in combination with other anticancer agents.

Clinical applications of the camptothecins.

The camptothecin topoisomerase I-targeting agents are new class of antitumor drugs with demonstrated clinical activity in human malignancies, such as colorectal cancer and ovarian cancer. Currently, irinotecan and topotecan are the most widely used camptothecin analogs in clinical use and clinical trials are ongoing to better characterize their spectra of clinical activity, to determine their optimal schedules of administration and to define their use in combination with other chemotherapeutic agents. Newer camptothecin analogs in clinical development, such as 9-aminocamptothecin, 9-nitrocamptothecin, GI147211 and DX-8951f, are also being studied to determine if they have improved toxicity and efficacy profiles compared with existing analogs.

Antifolates in clinical development.

Many novel antifolate compounds with unique pharmacologic properties are currently in clinical development. These newer antifolates differ from methotrexate, the most widely used and studied drug in this class, in terms of their lipid solubility and cellular transport affinity, their level of polyglutamation, and their specificity for inhibiting folate-dependent enzymes, such as dihydrofolate reductase, thymidylate synthase, or glycinamide ribonucleotide formyltransferase. The current status (ie, mechanism of action, clinical response rates, and toxicity) of some of the newer antifolate compounds presently in clinical testing, including edatrexate, piritrexim, raltritrexed, LY 231514, AG337, AG331, 1843U89, ZD 9331, and lometrexol, is reviewed.

Clinical status and optimal use of topotecan.

Topotecan (Hycamtin) is a promising new topoisomerase I-targeting anticancer agent that first entered clinical trials in 1989 under National Cancer Institute sponsorship in collaboration with SmithKline Beecham. In 1996, it was approved for use by the United States Food and Drug Administration (FDA) for previously treated patients with advanced ovarian cancer. For these patients, topotecan provides another therapeutic option upon disease progression after initial platinum-based chemotherapy.

Microbiology of nonbullous impetigo.

Our objective was to establish the aerobic and anaerobic microbiology of nonbullous impetigo (NI) in children. We used a retrospective review of clinical microbiology laboratory and patients' records. Specimens were obtained from 40 patients with NI lesions and showed bacterial growth.

New Antifolates: Pharmacology and Clinical Applications.

Many new antifolate compounds with unique clinical properties are currently in clinical development. Some of these agents have been rationally designed to circumvent known mechanisms of resistance to methotrexate, the most useful and extensively studied antifolate in clinical practice. Resistance to methotrexate can result from decreased active transport into cells, decreased polyglutamation resulting in enhanced drug efflux from cells, mutations in dihydrofolate reductase which reduce drug binding affinity, and increased expression of dihydrofolate reductase due to gene amplification or increased translational efficiency.

Chlamydial psittacosis during pregnancy: a case report.

Background: Chlamydia psittaci infection typically causes a mild influenza-like illness in humans. However, during pregnancy, this disease may present with severe headache, hypoxemia, thrombocytopenia, anemia, hepatic dysfunction, and disseminated intravascular coagulation. Limited reports of ovine-acquired psittacosis indicate appreciable maternal-fetal morbidity and mortality.

New antifolates in clinical development.

Numerous new antifolate drugs have been developed in an attempt to overcome the potential mechanisms of tumor cell resistance to methotrexate, which can include decreased drug transport into cells; decreased polyglutamation, leading to increased drug efflux from cells; decreased drug affinity for folate-dependent enzymes; mutations of dihydrofolate reductase (DHFR), a key enzyme required for the maintenance of adequate intracellular reduced folate levels that is inhibited by methotrexate; and increased expression of the DHFR protein. Promising antifolate compounds undergoing clinical testing as anticancer agents include trimetrexate (which was recently approved by the FDA for the treatment of Pneumocystis carinii pneumonia), edatrexate, piritrexim, Tomudex, and lometrexol. The mechanisms of action, dosage, pharmacokinetics, clinical toxicity, and antitumor activity of these drugs are profiled.

Cloning and characterization of cbl-b: a SH3 binding protein with homology to the c-cbl proto-oncogene.

We have cloned a new gene, cbl-b, with homology to the c-cbl proto-oncogene. A large protein is predicted (approx. MW 108,000) that has a proline rich domain, a nuclear localization signal, a C3HC4 zinc finger and a putative leucine zipper.

Granulosa cell tumor of the ovary associated with antecedent tamoxifen use.

Background: Increased attention has been focused recently on the estrogenic effects of tamoxifen. Review of the literature reveals an association between tamoxifen use and gynecologic tumors.

Case: A 52-year-old postmenopausal woman was treated with tamoxifen for stage II estrogen receptor-positive breast carcinoma.

Complete migration of peritoneal shunt tubing to the scalp.

The entire length of distal tubing from a ventriculoperitoneal shunt was found to have migrated into the subgaleal space, and resulted in a shunt obstruction. Upward migration of distal shunt catheters has rarely been reported, but probably involves patient motion that creates a "windlass" effect. Cephaled migration requires a potential space (subgaleal or ventricular) and no resistance to movement of the tubing.

Highly elevated CA125 and tubo-ovarian abscess mimicking ovarian carcinoma.

Elevated serum CA125 levels may be caused by any condition which produces peritoneal irritation as well as by the presence of various malignancies. This report of a case with atypical presentation of tubo-ovarian abscess and CA125 level of 1,160 U/ml serves to re-emphasize cautious operative planning in patients desirous of reproductive capability in the face of findings highly consistent with probable malignancy. This is the highest reported serum CA125 level in a reproductive age woman with well-documented reversible benign disease.

A comparison of solid intraventricular and dissociated intraparenchymal fetal substantia nigra grafts in a rat model of Parkinson's disease: impaired graft survival is associated with high baseline rotational behavior.

It has been established that substantia nigra (SN) grafts can produce a behavioral effect in animal models of Parkinson's disease when transplanted either into the lateral ventricles as solid tissue fragments or directly into the striatum as dissociated cells. These two transplantation methods (solid-intraventricular and dissociated-intraparenchymal) were directly compared in the present study. Adult male rats received unilateral SN lesions by stereotaxic injection of 6-hydroxydopamine.

Malignant peripheral nerve sheath tumors. A clinicopathologic study of 28 cases.

Background: In order to improve management, the files and tissue sections of 28 cases of malignant peripheral nerve sheath tumors (MPNST) diagnosed at the University of Virginia Health Sciences Center between 1960 and 1990 were reviewed.

Methods: Clinical data tabulated included age, sex, race, the presence or absence of von Recklinghausen neurofibromatosis type 1 (NF-1), tumor size, tumor location, type of treatment, and status of surgical margins. Pathologic study included assessment of mitotic rate, divergent differentiation, cellular atypia, necrosis, and vascular reaction.

Spontaneous cerebrospinal fluid rhinorrhea.

The diagnosis of CSF rhinorrhea requires the performance of a thorough history and physical examination. Often no objective findings can be found and further evaluation will be required. In our experience, metrizamide CT cisternography yields the most information for localization of the fistula.