The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin--the Aprepitant Protocol 052 Study Group.

PURPOSE: In early clinical trials with patients receiving highly emetogenic chemotherapy, the neurokinin antagonist aprepitant significantly enhanced the efficacy of a standard antiemetic regimen consisting of a type-three 5-hydroxytryptamine antagonist and a corticosteroid. This multicenter, randomized, double-blind, placebo-controlled phase III study was performed to establish definitively the superiority of the aprepitant regimen versus standard therapy in the prevention of chemotherapy-induced nausea and vomiting (CINV). PATIENTS AND METHODS: Patients receiving cisplatin > or = 70 mg/m2 for the first time were given either standard therapy (ondansetron and dexamethasone on day 1; dexamethasone on days 2 to 4) or an aprepitant regimen (aprepitant plus ondansetron and dexamethasone on day 1; aprepitant and dexamethasone on days 2 to 3; dexamethasone on day 4). Patients recorded nausea and vomiting episodes in a diary. The primary end point was complete response (no emesis and no rescue therapy) on days 1 to 5 postcisplatin, analyzed by a modified intent-to-treat approach. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments. RESULTS: The percentage of patients with complete response on days 1 to 5 was significantly higher in the aprepitant group (72.7% [n = 260] v 52.3% in the standard therapy group [n = 260]), as were the percentages on day 1, and especially on days 2 to 5 (P <.001 for all three comparisons). CONCLUSION: Compared with standard dual therapy, addition of aprepitant was generally well tolerated and provided consistently superior protection against CINV in patients receiving highly emetogenic cisplatin-based chemotherapy.     

A phase I study of SR-4554 via intravenous administration for noninvasive investigation of tumor hypoxia by magnetic resonance spectroscopy in patients with malignancy.

PURPOSE: To perform a Phase I study of SR-4554, a fluorinated 2-nitroimidazole noninvasive probe of tumor hypoxia detected by (19)F magnetic resonance spectroscopy (MRS). EXPERIMENTAL DESIGN: SR-4554 administration, on days 1 and 8, was followed by plasma sampling for pharmacokinetic studies and by three MRS studies performed over 24 h on days 8 and 9. Unlocalized MR spectra were acquired from tumor (10- or 16-cm dual resonant 1H/19F surface coil; 1.5 T Siemens Vision MR system; 2048 transients acquired over 34 min; 1.28-ms adiabatic pulse; repetition time, 1 s). Plasma drug concentrations were measured with a validated high-performance liquid chromatography method. Noncompartmental pharmacokinetic analysis was performed. RESULTS: Eight patients underwent pharmacokinetic studies, receiving doses of SR-4554 of 400-1600 mg/m(2). Peak plasma concentrations increased linearly with the SR-4554 dose (r(2) = 0.80; P = 0.0002). The plasma elimination half-life was relatively short (mean +/- SD, 3.28 +/- 0.59 h), and plasma clearance was quite rapid (mean +/- SD, 12.8 +/- 3.3 liters/h). Urinary recovery was generally high. SR-4554 was well tolerated. A single patient experienced dose-limiting toxicity (nausea and vomiting) at 1600 mg/m(2). The maximum tolerated dose was 1400 mg/m(2). SR-4554 was detected spectroscopically in tumors immediately after infusion at doses of 400-1600 mg/m(2). At the highest dose (1600 mg/m(2)), SR-4554 was detectable in tumor at 8 h, but not at 27 h. CONCLUSIONS: SR-4554 has plasma pharmacokinetic and toxicity profiles suitable for use as a hypoxia probe. It can be detected in tumors by unlocalized MRS. Additional clinical studies are warranted.     

First results of a phase I/II dose escalation trial in non-small cell lung cancer using three-dimensional conformal radiotherapy.

PURPOSE: To evaluate the feasibility of dose escalation in non-small cell lung cancer (NSCLC) using three-dimensional conformal radiation therapy. PATIENTS AND METHODS: The main eligibility criteria of the trial were: pathologically proven inoperable NSCLC, ECOG performance status or=grade 3 (SWOG), grade 3 early and grade 2 late esophageal toxicity or any other (RTOG) grade 3 or 4 complications). RESULTS: Fifty-five patients were included. Tumor stage was I/II in 47%, IIIA in 33% and IIIB in 20%. The majority of the patients received a dose of 74.3 Gy (n=17) or 81.0 Gy (n=23). Radiation pneumonitis occurred in seven patients: four patients developed a grade 2, two patients grade 3 and one patient a grade 4. Esophageal toxicity was mild. In 50 patients tumor response at 3 months follow-up was evaluable. In six patients a complete response was recorded, in 38 a partial response, five patients had stable disease and one patient experienced progressive disease. Only one patient developed an isolated failure in an uninvolved nodal area. So far the radiation dose was safely escalated to 87.8 Gy in group 1 (lowest rMLD), 81.0 Gy in groups 2 and 3 and 74.3 Gy in group 4. CONCLUSION: Three-dimensional conformal radiotherapy enables significant dose escalation in NSCLC. The maximum tolerable dose has not yet been reached in any risk group.     

Magnetic resonance imaging compared with echocardiography in the evaluation of pulmonary artery abnormalities in children with tetralogy of Fallot following palliative and corrective surgery

Background. Abnormalities of the pulmonary arteries following palliative or corrective surgery for tetralogy of Fallot (TOF) are common. Our purpose was to compare the usefulness of magnetic resonance imaging (MRI) and echocardiography in the post- operative evaluation of the pulmonary arteries in children with TOF. Objective. Our hypothesis was that MRI is more sensitive than echocardiography in the detection of branch pulmonary artery abnormalities in children with TOF. Materials and methods. Pulmonary artery MRI and echocardiography were performed in 20 children following palliative and/or corrective surgery for TOF. MRI and echocardiography were compared in their ability to detect abnormalities of the pulmonary arteries. Angiographic or surgical correlation was available in 15 children. A perfusion scan for confirmation of pulmonary artery patency was available in one additional child. Results. Abnormalities of the branch pulmonary arteries identified by MRI included: absence or occlusion (2), focal stenosis (15), hypoplasia (2), aneurysm (1), and non-confluence (1). Echocardiography could not adequately visualize the right and left branch pulmonary arteries in eight and ten children, respectively. Echocardiography missed stenosis in 13 branch pulmonary arteries, patency of hypoplastic pulmonary arteries in two children, non-confluence of the pulmonary arteries in one child, and a left pulmonary artery aneurysm in one child. Abnormalities identified by MRI were confirmed in 16 children by angiography, surgery or perfusion scan. Conclusion. MRI is more sensitive than echocardiography for the evaluation of branch pulmonary artery abnormalities in children following surgery for TOF. Received: 13 January 1997 Accepted: 31 July 1997     

Interleukin-8 Concentration Predicts the Neutrophil Count in Middle Ear Effusion

Interleukin-8 (IL-8), a potent neutrophilic chemoattractant and inflammatory cytokine, is present in middle ear effusions (MEEs) of children with otitis media and is thought to be responsible for the accumulation of neutrophils in MEEs. We hypothesized that IL-8 concentration predicts the total number and proportion of neutrophils in MEEs. IL-8 concentration and total and differential cell counts were measured in MEEs of children undergoing tympanostomy tube placement for otitis media. IL-8 was present in 80 (98%) of 82 effusions. The mean ± SEM value for IL-8 was 7342 ± 847 pg/mL. The mean ± SEM count and percentage of neutrophils were 1.34 × 10⁶ ± 3.44 × 10⁵ and 70.6 ± 3.1%, respectively. IL-8 concentrations correlated positively with the total number(r = +0.30; P = 0.02) and percentage of neutrophils(r= +0.32; P = 0.01) in the effusion. Additionally, purulent effusions had greater IL-8 concentrations (P = 0.003) and greater neutrophil count (P = 0.03) than mucoid or serous effusions. We conclude that IL-8 is consistently present in MEEs of children and IL-8 concentration predicts the total number and proportion of neutrophils. Furthermore, IL-8 concentration and the total number of neutrophils correlate positively with the type of effusion. These results support the hypothesis that IL-8 recruits neutrophils to the middle ear in MEEs.     

Prognostic Indicators for Squamous Cell Carcinoma of the Oral Cavity: A Clinicopathologic Correlation

Fifty-three patients with T1 squamous cell cancer of the floor of mouth and ventral surface of the tongue with a known clinical outcome were retrospectively analyzed and arbitrarily divided into “aggressive” and “nonaggressive” groups based on their clinical behavior. Various host and tumor factors were then evaluated in an attempt to determine whether the tumor behavior could have been predicted. The paraffin-embedded tumor specimens were evaluated for tumor differentiation, tumor thickness and tumor invasion, microvessel density, and p53 expression. In addition, a composite morphologic grading score was obtained by combining cell differentiation, nuclear polymorphism, mitosis activity, depth of infiltration, type of infiltration, and lymphatic infiltration. No single technique appeared capable of identifying “aggressive” behavior, although possibly an evaluation of composite factors might show promise in the future.     

Wound Complications Associated With Brachytherapy for Primary or Salvage Treatment of Head and Neck Cancer

Brachytherapy can be employed in the primary or salvage treatment of head and neck cancer. The advantage of brachytherapy is the stereotactic limitation of radiation exposure to noninvolved tissues. Wound complications associated with brachytherapy have been discussed only sporadically in the literature. This retrospective study examines 28 patients, 20 for initial treatment and eight for salvage, with varying site and stage head and neck cancer treated with brachytherapy in addition to external beam radiation therapy and/or surgery. The overall complication rate was 50% (14/28), with infection and minor flap breakdown being the most common problems. Tumor site in the primary treatment group was the only significant factor in wound complications. In the salvage group complications were minor and primarily related to flap coverage of brachytherapy catheters.     

A double-blind randomised controlled trial of the effects of medroxyprogesterone acetate on bone density of women taking oestrogen replacement therapy

Objective To assess the effects of medroxyprogesterone acetate on bone density in women who have had a hysterectomy
Design Randomised, double-blind, placebo-controlled trial of medroxyprogesterone acetate 10 mg, 20 mg or placebo as an adjunct to oestrogen therapy.
Participants One hundred and twenty-three women, aged 18 to 45 years and currently receiving daily oestrogen, who presented at a university-based rheumatology practice.
Interventions The women were randomly assigned to receive either medroxyprogesterone acetate 10 mg, 20 mg or placebo daily beginning on day 15 of each month for one year. Forty-one women were randomised into each group.
Main outcome measure The primary outcome measurement was the percentage of change from baseline in bone mineral density of the lumbar spine (L2–L4). Secondary outcome measures included differences in femoral neck bone density, cholesterol and triglyceride levels between groups.
Results At one year, change in bone mineral density did not differ between either the treatment or placebo groups. Medroxyprogesterone acetate 20 mg and 10 mg led to statistically significant reductions in very low density lipoprotein cholesterol, total triglycerides, and very low density lipoprotein triglycerides when compared with placebo. Medroxyprogesterone acetate 20 mg also led to a statistically significant reduction in high density lipoprotein cholesterol, high density lipo-protein-2 cholesterol, and high density lipoprotein-2 triglycerides.
Conclusions Medroxyprogesterone acetate at either dose as an adjunct to oestrogen did not improve bone mineral density at one year when compared with placebo. Medroxyprogesterone acetate 10 mg may not adversely affect lipids. Medroxyprogesterone acetate 20 mg, however, did reduce high density lipoprotein cholestrol and therefore may increase cardiovascular risk.     

Subcutaneous estradiol pellets for endometrial preparation in donor oocyte recipients with a poor endometrial response

Purpose: The purpose of this study was to evaluate the clinical effectiveness of subcutaneous estradiol pellets in donor oocyte recipients with an inadequate endometrial response. Methods: The subjects were 13 women with ovarian failure and a maximal endometrial thickness <10 mm on standard estrogen regimens, as demonstrated during mock and/or prior oocyte donation cycles. They underwent pellet implantation (100–250 mg of estradiol) 6–13 weeks before oocyte donation. Results: Maximal (mean ± SD) endometrial thickness was 8.7±1.5 mm on standard regimens, in contrast to 11.7± 1.8 mm on pellets, while estradiol levels were 674±844 and 815±706 pg/ml, respectively. The estradiol:estrone ratio on pellets was >1. There was 1 pregnancy with early loss during 10 cycles on other estrogen regimens and 12 pregnancies during 19 cycles on pellets. The pregnancy and implantation rates were, respectively, 63 and 27% on pellets and 41 and 14% on standard regimens in historical controls. Conclusions: We conclude that estradiol pellets after a single administration provide constant estradiol levels extending into the first trimester of pregnancy, a physiologic estradiol:estrone ratio, and a better endometrial response than standard estrogen regimens. Implantation and pregnancy rates are higher. This approach may be especially suitable for recipients with a poor endometrial response. Presented at the IXth World Congress on In Vitro Fertilization and Assisted Reproduction, Vienna, Austria, April 3, 1995, and the 51st Annual Meeting of the American Society for Reproductive Medicine, Seattle, Washington, October 7–12, 1995.     

Molecular Genetics in the Diagnosis and Prognosis of Solid Pediatric Tumors

The field of molecular genetics continues to see an ever increasing number of applications to pediatric tumor analysis. Studies in pediatric tumors have identified novel genes and other genetic changes, a large number of which reflect one of the following mechanisms: (1) activation of proto-oncogenes; (2) loss of tumor suppressor genes; or (3) creation of novel fusion proteins. At least one of these mechanisms is operational in each of the following pediatric tumors: neuroblastoma, Ewing sarcoma and peripheral primitive neuroectodermal tumor (pPNET), intra-abdominal desmoplastic small-cell tumor, rhabdomyosarcoma, synovial sarcoma, and Wilms tumor. Out of this research has come not only an increased understanding of oncogenesis but also, for each of the tumors listed above, diagnostic and/or prognostic markers that can be used by the pathologist and oncologist to improve overall patient management. Received November 20, 1997; accepted April 20, 1998.