A phase II pilot study of KW-2189 in patients with advanced renal cell carcinoma.

BACKGROUND: KW-2189 is a semi-synthetic, water-soluble analog of duocarmycin B2, a new class of potent antitumor antibiotics produced by streptomyces, with improved in vitro antitumor potency. PATIENTS AND METHODS: Forty patients with pathologically confirmed metastatic renal cell carcinoma were treated in this multicenter, open-label phase II trial. All patients received 0.4 mg/m2 KW-2189 as an i.v. infusion for Cycle I. Cycles were repeated every 5 to 6 weeks with escalations to 0.5 mg/m2 in the absence of significant toxicity or disease progression. RESULTS: No patient had an objective response. The most common drug-related toxicity was hematological-delayed neutropenia and thrombocytopenia, with recovery by week 6. Non-hematologic toxicity consisted of mild to moderate fatigue, nausea and vomiting, and anorexia that was generally manageable. CONCLUSIONS: KW-2189 in this dose and schedule has a predictable safety profile of reversible myelosuppression. No activity in metastatic renal cell carcinoma was demonstrated.

The role of endoscopic sinus surgery in patients with acquired immune deficiency syndrome.

PURPOSE: Increasingly, otolaryngologists are treating patients with acquired immunodeficiency syndrome (AIDS) who suffer from associated sinusitis refractory to medical therapy. Despite this trend, few reports in the literature detail the mode of surgical therapy, pathogens, and outcome in this patient population. Our aim in this study was to describe our experience in treating these patients, with particular attention to surgical outcome and pathogens. PATIENTS AND METHODS: We reviewed our experience with performing sinus surgery in 33 AIDS patients. Endoscopic sinus procedures were performed in 24 patients, while the remaining nine patients underwent nasal antral windows and/or Caldwell-Luc operations. Follow-up information was obtained in 16 of the 24 patients who underwent endoscopic sinus surgery. RESULTS: At an average follow-up time of 16 months, 14 of the endoscopic sinus surgery patients reported improvement from their preoperative condition. Thirty-seven pathogens were identified in 23 patients. A larger percentage of nontraditional pathogens was found in these patients, which suggests a larger role for microbiologic diagnosis and treatment versus empiric therapy. CONCLUSION: Patients with AIDS and chronic sinusitis may benefit from endoscopic sinus procedures.

Asymptomatic congenital syphilis and auditory brainstem response.

Untreated congenital syphilis is a known cause of hearing loss. In order to ascertain if infants are at risk of hearing loss at birth, 75 neonates with serologic evidence of syphilis and APGAR scores greater than 9 at 5 min were examined by auditory brainstem response (ABR) audiometry. All of the infants had normal ABRs. Ophthalmologic examination revealed no evidence of interstitial keratitis. Lumbar puncture was attempted on all the neonates. Cerebrospinal fluid (CSF) was successfully obtained from 41 infants and revealed no abnormalities. This study demonstrates that asymptomatic infants with serologic evidence of syphilis do not require audiologic evaluation in the neonatal period.

Has informed consent finally arrived in Australia? A comment on the law following the decision of the High Court of Australia in Rogers v. Whitaker.

A struggle is going on all over the world between medical paternalism and patient autonomy. The battlegrounds include clinics, hospitals, academic settings and the courts. The High Court has awarded the most recent round, six to nothing, to autonomy, but the fight is by no means over. The judgements, the current law in Australia, and the implications for medical practice are discussed.

Otologic neurotologic manifestations of HIV-related disease.

Human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS), has reached worldwide epidemic proportions and is increasing. Otologists, neurotologists, and audiologists practicing in metropolitan centers in North America can expect to encounter patients with HIV-related illnesses, including patients with AIDS-related complex (ARC) and AIDS. Five representative cases are presented: chronic otitis media, facial palsy, Gradenigo's syndrome with facial paralysis, otosyphilis, and Kaposi sarcoma of the mastoid. The common link in all cases was HIV infection. This presentation discusses the management of several HIV-infected patients with otologic and neurotologic findings. HIV infection has extended to all parts of North America. The worldwide incidence is increasing. As the epidemic continues to unfold, new challenges to both the diagnosis and treatment of otologic and neurotologic disease in HIV-positive patients will confront the audiologist and otolaryngologist. Recommendations for the safety of the examining audiologist and treating physician are given.

Urgent adenotonsillectomy for upper airway obstruction.

Adenotonsillar hypertrophy has been documented to cause chronic upper airway obstruction resulting in cardiopulmonary sequelae in children. It has been less recognized that long-term adenotonsillar hypertrophy may additionally cause acute, life-threatening airway obstruction. A review of 5000 adenotonsillectomies performed at 3 New York Medical College affiliated hospitals from 1982 to 1989 showed 6 pediatric patients with progressive upper airway obstruction severe enough to necessitate intubation in the emergency room or operating room, and subsequent urgent adenotonsillectomy after cardiorespiratory stabilization. Patients were monitored in the ICU with pre- and postoperative blood gases. Observations of cyanosis, cor pulmonale, and use of accessory respiratory muscles were carefully recorded. This study illustrates that life-threatening upper airway obstruction may be due to chronic adenotonsillar enlargement and require treatment by urgent adenotonsillectomy.

Otolaryngologic manifestations of child abuse.

Currently, awareness is growing of child abuse in the medical and lay communities. To familiarize otolaryngologists with the head and neck findings in abused children, we retrospectively analyzed 85 patients admitted to an inner-city hospital with the diagnosis of abuse or neglect. Forty-eight children (56%) had abnormalities within the head and neck region. Excluding coincidental findings, 31 children (36%) had findings that could be directly linked to physical abuse or neglect. The face was the region with the most abnormal findings in our study (25 children [30%]). Soft-tissue findings were the most numerous (27 children [32%]). The literature is reviewed on the subject of otolaryngologic manifestations of abuse.

Synovial sarcoma of the head and neck.

Primary synovial sarcoma is an unusual tumor of the head and neck. Fewer than 75 cases have been reported in the literature. We have treated 7 additional cases; 3 in the hypopharynx, 2 in the parapharyngeal space, 1 in the oral pharynx and 1 in the posterior triangle of the neck. An enlarging cervical mass, voice change, and dysphagia were among the presenting complaints. CT revealed solitary nonhomogenous tumors from 3 to 7 cm in diameter. Microscopically, all cases showed a biphasic cellular pattern verified by immunohistochemical staining. Multimodality treatment consisted of surgery and postoperative radiation therapy with 3 patients receiving chemotherapy. Although the original pathology report was incorrect in 3 cases, clinical suspicion for synovial sarcoma ensured proper diagnosis.

Fine-needle aspiration of diffuse cervical lymphadenopathy in patients with acquired immunodeficiency syndrome.

Although diffuse cervical lymphadenopathy is one of the earliest and most common findings in patients with AIDS, the appropriate diagnostic approach in these patients has yet to be determined. Fine-needle aspiration (FNA) was performed on 26 patients with AIDS in order to evaluate the role of FNA in patients with diffuse cervical adenopathy. Specimens were sent for cytology, bacterial culture, fungal culture, and acid-fast smear and culture. Ten patients had positive findings, including toxoplasmosis, histoplasmosis, tuberculosis, atypical mycobacterium, and methicillin-resistant staphylococcal infection. All patients with either unilateral adenopathy or lymph nodes 3 cm or larger had positive aspirates. A statistically significant difference between patients with lymph nodes smaller than 2 cm and those with nodes larger than 2 cm was found. Fine-needle aspiration of a representative node in patients with AIDS may allow prompt diagnosis of diffuse lymphadenopathy. Rapid initiation of appropriate treatment can lead to symptomatic improvement. The need for excisional biopsy of involved lymph nodes may be obviated. Fine-needle aspiration is recommended as a diagnostic tool in selected patients with diffuse cervical lymphadenopathy and AIDS.

Evidence for impaired mitoxantrone and vinblastine binding in P388 murine leukemia cells with multidrug resistance.

Multidrug resistance is associated with a P170 glycoprotein efflux pump that limits net drug accumulation in resistant cell lines. Other evidence has suggested that diminished net drug uptake in multidrug resistant (MDR) cells is due to decreased drug binding as well. To assess the contribution of binding differences to net drug accumulation and retention in MDR cells, mitoxantrone and vinblastine, two agents commonly associated with the MDR phenotype but with different mechanisms of action and intracellular binding sites, were studied in P388 murine leukemia cells. For both drugs, resistance was associated with a marked reduction in tightly bound drug which can account for the diminished net drug accumulation in this cell line; even at 1 microM vinblastine when the exchangeable component was one-half that of the sensitive cells, the nonexchangeable component was only one-seventh. For mitoxantrone, the exchangeable drug component was greater in resistant cells at low drug levels (1 microM) and similar at high drug levels (10 microM). For vinblastine, the exchangeable drug component was decreased in the resistant cells at 1 microM, but the difference compared to sensitive cells became neglible at 10 microM. The data indicate that diminished net drug uptake in the P388 MDR cell line was associated with a marked decrease in tightly bound, i.e. nonexchangeable, drug fractions for both mitoxantrone and vinblastine. Therefore, alterations in intracellular binding are in important factor in the decreased cellular uptake and retention of drugs in the multidrug resistance phenomenon. The relationship between these changes and the P170 efflux pump requires further clarification.

Medially based horizontal nasolabial flaps for reconstruction of columellar defects.

Reconstruction of columellar defects continues to be a surgical challenge. We present the results of two child-abuse patients who were successfully treated with a technique in which medially based bilateral horizontal nasolabial flaps were used to reconstruct total columellar loss. Our technique provides adequate tissue with minimal cosmetic deformity. It also obviates the need for multiple staged procedures. We recommend the use of this method for repair of either partial or total columellar defects secondary to trauma or infection.

Head and neck manifestations of the acquired immunodeficiency syndrome in children.

The head-and-neck manifestations of HIV infection in children are very different from those in the adult population. Recurrent bacterial and viral infections are common manifestations, and persistent sinusitis or otitis media should make the otolaryngologist suspicious of HIV infection if the child has been exposed to the virus. Other common problems include mucocutaneous and esophageal candidiasis, recurrent herpes I and II and zoster infections, parotid swelling, and cervical lymphadeopathy.

Delayed airway obstruction and neck abscess following manual strangulation injury.

Few reports describing manual strangulation injury to the neck are found in the otolaryngologic literature. Since most victims sustain immediate fatal asphyxiation, brain anoxia, or cardiac arrest, they are usually examined by a forensic pathologist. When strangulation attempts are nonfatal, neck injuries can lead to delayed airway obstruction. If not managed in a timely fashion, these injuries can be fatal or cause permanent laryngotracheal sequelae. We describe a patient who 36 hours following manual strangulation developed acute upper airway obstruction and neck abscess necessitating tracheotomy, neck exploration, and drainage. Patients suffering this unique type of compression injury may present initially with deceptively benign symptoms and signs. We discuss the overall management of these patients, stressing the need for early imaging studies, endoscopic assessment, and continued airway monitoring in an intensive care unit.

Membrane protein changes in an L1210 leukemia cell line with a translocation defect in the methotrexate-tetrahydrofolate cofactor transport carrier.

We report on membrane protein changes in an L1210 leukemia cell line with a highly specific defect in the function of the methotrexate (MTX)-tetrahydrofolate cofactor transport carrier. This clonal line, MTXrA, made 100-fold resistant to MTX, was derived in a single step and exhibited stable resistance over 120 generations in the absence of drug. The transport defect was associated with a 10-fold decrease in influx Vmax without a change in influx Km. There was no difference between the MTXrA and parent lines in the levels or affinities of specific cell surface binders for MTX nor in the labeling of the 44-kDa membrane protein upon treatment with the specific affinity label, N-hydroxysuccinimide ester of tritiated MTX. Consistent with impaired carrier function was the observation that trans-stimulation of MTX influx by intracellular 5-formyltetrahydrofolate observed in the parent line was not demonstrated in the MTXrA line. The transport defect was highly specific for the MTX-tetrahydrofolate cofactor transport carrier. Initial uptake rates for 5-fluoro-2'-deoxyuridine and 2-deoxyglucose were unchanged and influx and net transport of alpha-aminoisobutyric acid were, in fact, increased. There was no cross-resistance of this line to phenylalanine mustard or cytosine arabinoside, agents that utilize specific amino acid and nucleoside transport carriers, respectively. SDS-polyacrylamide gel electrophoresis of purified plasma membrane preparations stained with Coomassie Blue revealed several protein differences between the parental and MTXrA lines. Most prominent is a band at approximately 190 kDa which ran with slightly greater mobility than a lesser staining band in the parent line. [3H]Borohydride labeling of cells also identified a distinct protein peak in the MTXrA line at approximately 190 kDa eliminated by prior treatment of cells with neuraminidase. Absence of expression of protein or mRNA related to the multidrug resistance gene as well as lack of cross-resistance to daunorubicin or trimetrexate indicate that this mechanism of resistance to MTX is completely unrelated to the multidrug resistance phenomenon observed with high molecular weight heterocyclic compounds. These data represent the first demonstration of membrane protein differences in a highly resistant L1210 murine leukemia cell line with a marked unique defect in MTX transport which appears to be related to impaired mobility of the tetrahydrofolate-cofactor carrier. Further studies are now required to elucidate the possible role of one or more of these proteins in the transport defect.

Oropharyngeal angioedema associated with the use of angiotensin-converting enzyme inhibitors.

Angioedema that occurs in the head and neck may be a serious and possibly life-threatening condition. We present two cases of oropharyngeal angioedema associated with the use of angiotensin-converting enzyme inhibitors in patients with no underlying renal failure. Angiotensin-converting enzyme-inhibiting agents are now commonly used to control hypertension. Treatment of acquired angioedema is directed first at protecting the airway by careful observation, intubation, or if necessary, tracheostomy. The causative agent is withdrawn, and the patient is treated with antihistamines and steroids until the acute episode resolves. Although not used in our patients, the treatment of angioedema with subcutaneous epinephrine has been described. As more patients are treated with angiotensin-converting enzyme inhibitors, it becomes essential for the otolaryngologist to become aware of this potentially life-threatening complication.