Genetic testing for hereditary cancer predisposition: BRCA1/2, Lynch syndrome, and beyond.

Obstetrician/gynecologists and gynecologic oncologists serve an integral role in the care of women at increased hereditary risk of cancer. Their contribution includes initial identification of high risk patients, screening procedures like bimanual exam, trans-vaginal ultrasound and endometrial biopsy, prophylaxis via TAH and/or BSO, and chemoprevention. Further, gynecologists also serve a central role in the management of the secondary repercussions of efforts to mitigate increased cancer risks, including vasomotor symptoms, sexual function, bone health, cardiovascular disease, and mental health. The past several years has seen multiple new high and moderate penetrance genes introduced into the clinical care of women at increased risk of gynecologic malignancy. Awareness of these new genes and the availability of new multi-gene panel tests is critical for providers on the front-line of women's health.

Post-epidural analgesia spinal cord infarction: MRI correlation.

Permanent neurological deficits after epidural analgesia are rare, but have long been believed to be caused by cord ischaemia when no obvious cause is demonstrable. The mechanisms of this injury are uncertain, but a literature review suggests important risk factors. We report a first case of extensive spinal cord infarction confirmed by magnetic resonance imaging (MRI) following post-thoracotomy epidural analgesia and review the literature to explain the mechanism underlying this devastating complication.

Further experience with Botox injection for tracheoesophageal speech failure.

BACKGROUND: Some patients fail to acquire tracheoesophageal (TE) speech after laryngectomy because of pharyngeal constrictor hypertonicity. Botox injection relieves hypertonicity, but there are little objective data regarding outcomes, duration of effect, and reinjection rates. METHODS: Hypertonicity was identified by means of insufflation testing and confirmed videofluoroscopically in 23 unsuccessful TE speakers. Each patient received an EMG-guided Botox injection. Additional injections were offered if the first injection failed to produce fluent speech. RESULTS: Overall, 20 of 23 patients (87%) achieved fluent TE speech production after Botox injections; 5 after additional injections. Two patients declined further intervention, and 1 failed to achieve fluent TE speech production even after 3 Botox injections. The longest sustained effect was 37 months, the shortest was 5 months for 1 patient who required reinjection of Botox to maintain her TE speech production. CONCLUSIONS: Botox injection relieves constrictor hypertonicity in selected cases of TE speech failure with little need for reinjection to maintain long-term speech success.

Phase II trial and pharmacokinetic evaluation of cytosine arabinoside for leptomeningeal metastases from breast cancer.

PURPOSE: To determine the efficacy and pharmacokinetics of intraventricular cytosine arabinoside (Ara-C) as front-line treatment for leptomeningeal metastases from breast cancer. METHODS: Ten patients newly diagnosed with leptomeningeal metastases (LMM) from breast cancer were treated with 100 mg intraventricular cytosine arabinoside (IVT Ara-C) via an Ommaya reservoir. Treatment was administered three times a week for 2 weeks, then once a week for 4 weeks, and then once every 6 weeks for four cycles to responding patients. Nine patients were evaluable clinically, and seven patients underwent testing to determine the pharmacokinetic profile of Ara-C in the cerebrospinal fluid (CSF). RESULTS: Two patients had partial responses lasting 9 and 40 weeks, respectively. Two other patients had stable disease. The median survival duration was 30 weeks (range: 5-58 weeks). Seven patients died from LMM. Acute toxic effects associated with IVT Ara-C included meningismus, nausea, vomiting, and myelosuppression. The median peak Ara-C level in CSF was 16.69+/-6.30 mM (SD). The half life for elimination was 1.45+/-0.61 h (SD) There was no drug accumulation between courses. Neuropsychological evaluations were completed in eight patients, six (75%) of whom had preexisting cognitive deficits. Their condition generally improved over the course of treatment until the LMM progressed. No neurotoxic side effects of IVT Ara-C were observed in the two patients who had normal baseline cognitive assessments. CONCLUSIONS: IVT Ara-C at this dose and schedule has minimal activity as initial treatment for LMM from breast cancer despite achievement of high peak levels of the drug in the cerebrospinal fluid. A liposomal Ara-C formulation is currently under investigation.

Carpal tunnel syndrome associated with interleukin-2 therapy.

BACKGROUND: Interleukin (IL-2) has been extensively used in our institution in the treatment of cancer and has protean neurologic side effects. Carpal tunnel syndrome developing in patients receiving IL-2 appears to have a good prognosis and may spare the patient unneeded investigation. METHODS: A retrospective evaluation was undertaken for all patients using our institution's Patient Studies database. The patients were examined and their charts reviewed. RESULTS: We found eight patients with renal cell carcinoma who developed carpal tunnel syndrome (CTS) during treatment with IL-2, fluorouracil (5-FU), and alpha-interferon (alpha-IFN). The symptoms were bilateral in five patients and all patients improved with cessation of therapy. Three patients had recurrent symptoms with subsequent courses of therapy. Symptoms occurred during or shortly after IL-2 infusion and resolved after therapy was completed with conservative management. The number of courses given did not seem to correlate with development of symptoms. Neurophysiologic studies demonstrated conduction velocity slowing without evidence of acute denervation. CONCLUSIONS: IL-2 can produce focal entrapment of the median nerve at the wrist, which reverses with drug withdrawal. IL-2 mediates the inflammatory response and can cause interstitial edema that likely causes CTS to develop in predisposed patients undergoing treatment.

Patients with malignant meningitis presenting with neuropsychiatric manifestations.

BACKGROUND: Malignant meningitis is often thought of as a late event in the course of cancer. At one time, it was thought to be rare, but it has been recognized more frequently in recent times. Clinical suspicion of malignant meningitis is prompted by neurologic symptoms and signs in patients at risk for this oncologic complication. Neuropsychiatric symptoms previously were not considered as presenting symptoms of malignant meningitis. METHODS: Three patients with cancer with no neurologic symptoms were examined for malignant meningitis based on neuropsychiatric symptoms. Cerebrospinal fluid was examined for malignant cells to confirm the diagnosis of malignant meningitis. RESULTS: The clinical presentation of malignant meningitis for three patients was neuropsychiatric. None of the patients had delirium during their initial presentation. CONCLUSIONS: It is important that clinicians recognize that psychiatric symptoms without neurologic findings may indicate malignant meningitis and that malignant meningitis needs to be included in the differential diagnosis of neuropsychiatric disorders in patients with cancer.

Neurologic complications of cytokine therapy.

There have been surprisingly few controlled studies of the central nervous system actions of cytokines in humans, although many clinical trials have briefly reported side effects of these drugs. Clinical trials using cytokines have chiefly involved patients with cancer, often at an advanced stage, and prospective formal neurologic assessment has been infrequent. In patients with malignancy, a host of variables can confound neurologic evaluation, including nutritional status, metastatic deposits, metabolic derangements, effects of former treatments, and infection. The effects of the cytokines on the central nervous system are multiple and limit their clinical use. Careful prospective clinical study of these agents is essential and may yield insights into their functions in the CNS and increase their efficacy as clinical tools.

Biology and treatment of gliomas.

This review discusses some of the recent advances in glioma research and treatment. Our understanding of the characteristics of these tumors has been strengthened by the application of molecular biologic and genetic techniques to pathologic grading and therapy outcome. Newer attempts to correlate imaging modalities to pathologic grading are also discussed. It is anticipated that these developments will strengthen our ability to design improved treatment strategies, an essential goal inasmuch as current treatment schemes have limited benefit. More work needs to be done to understand the biology of these tumors especially the complex interactions of their cytokine expression, multiplicity of genetic abnormalities, and their local environment. Only then will be able to develop improved therapeutic interventions.

Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer.

Taxol, an antimicrotubule agent, has shown promise for efficacy in treatment of breast cancer, but severe hypersensitivity reactions led to cessation of many phase I clinical trials. Consequently, investigators and the National Cancer Institute recommended that phase I and II studies of this agent use 24-hour infusions and antiallergic medications. Using a premedication regimen effective in preventing hypersensitivity reactions, we have performed a phase II trial of taxol in patients with metastatic breast cancer. Taxol was administered to 25 patients at a dose of 250 mg/m2 by 24-hour infusion every 21 days. These patients had received only one prior chemotherapy regimen, either adjuvant to surgery or for metastatic disease; all but two had received doxorubicin. In 60% of the patients, the dominant site of disease was the viscera. All patients were assessable. In April 1991, at a median time on study of 9 months (range, 5-13+ months), the objective response rate was 56% (12% complete and 44% partial; 95% confidence interval, 35%-76%). Disease progressed in only 8% of the patients. The median number of courses of therapy was 11. Granulocytopenia was the dose-limiting toxic effect, but neutropenia with fever occurred in only 5% of 232 courses. A chronic glove-and-stocking neuropathy developed in most patients, but no allergic reactions occurred. We conclude that taxol is an active agent in the treatment of metastatic breast cancer and that it warrants continued study. Currently, we are conducting a phase I trial of taxol plus doxorubicin. Future trials should address the optimal effective dose, the optimal sequencing of combinations, mechanisms of drug resistance in tumors, and dose-limiting toxic effects (particularly cardiac toxic effects of taxol given as a single agent or in drug combinations).

Persistent neurotoxicity of systemically administered interferon-alpha.

Fourteen cancer patients had evidence of persistent neurotoxicity of interferon-alpha therapy long after their treatment was discontinued. Although most of the cognitive symptoms were mild to moderate in severity, they were incapacitating to these individuals in their usual work. The neuropsychological test abnormalities were not attributable to subsequent therapy, disease status, or other medical problems. The pattern of deficits was consistent with frontal-subcortical dysfunction. Of the four patients who had follow-up assessment, two had improved and two had deteriorated. These findings suggest that in some cases interferon neurotoxicity is not reversible.