A phase I trial of ZD9331, a water-soluble, nonpolyglutamatable, thymidylate synthase inhibitor.

PURPOSE: ZD9331 is a novel, direct-acting antifolate cytotoxic that does not require polyglutamation for activity, and is a specific thymidylate synthase inhibitor. This Phase I trial aimed to determine the maximum tolerated dose of ZD9331, given as a 30-min i.v. infusion on days 1 and 8 of a 21-day cycle. Pharmacokinetic parameters and tumor response were also assessed. EXPERIMENTAL DESIGN: A total of 71 patients, with a range of solid malignancies and refractory to standard therapies (44% had received > or =3 prior chemotherapy regimens), were treated. The most common malignancies were colorectal cancer (35% of patients) and ovarian cancer (31%). ZD9331 was escalated from 4.8 mg/m(2)/day. RESULTS: Dose-limiting toxicity occurred at 162.5 mg/m(2) ZD9331, with grade 4 thrombocytopenia, grade 4 neutropenia lasting > or =7 days, and grade 3 nonhematologic toxicity. Plasma clearance of ZD9331 was slow and dose-dependent; however, ZD9331 pharmacokinetics were nonlinear. Pharmacodynamics of ZD9331 were determined by measurement of plasma deoxyuridine, which increased at all of the dose levels; dose-related increases in plasma deoxyuridine were significant (P = 0.003) on day 5. Stable disease was observed in 37% of patients; 23% of ovarian cancer patients had a > or =50% reduction in CA125 levels. CONCLUSIONS: The maximum tolerated dose of this schedule was 130 mg/m(2). The toxicity profile at this dose was acceptable, with 7 of 28 patients treated developing grade 3/4 neutropenia and thrombocytopenia, 2 grade 4 diarrhea, and 2 grade 3/4 rash. This schedule was convenient and demonstrated activity in extensively pretreated patients; therefore, this is the recommended dose for study in Phase II trials.     

Pyloric volume: an important factor in the surgeon’s ability to palpate the pyloric “olive” in hypertrophic pyloric stenosis

Objective. The objective of this study was to determine whether the size of the pyloric mass is one of the factors in the surgeon's ability to palpate the pyloric “olive”. Materials and methods. The ultrasonographic images and medical records of 60 infants with surgically confirmed hypertrophic pyloric stenosis (HPS) were reviewed. The pyloric diameter (PD) and pyloric length (PL) were measured and the pyloric volume (PV) was calculated using the equation PV = 1/4π× (PD)²× PL. Based on the pediatric surgeon's physical examination the infants were divided into two groups: those with and those without palpable pyloric masses. Results. Infants with a palpable pyloric mass had an average pyloric volume of 3.33 ± 1.76 mm³, which was statistically larger than those whose hypertrophied pylorus could not be palpated (average volume 2.59 ± 2.07 mm³, P < 0.01). There was no statistically significant age difference between the two groups. Conclusion. Clinical skill of the examiner and other clinical aspects (patient cooperation, etc.) determine palpability of the pylorus in HPS. The size of the hypertrophied pylorus is also an important factor affecting the clinican's ability to palpate the pyloric mass. Received: 29 December 1995 Accepted: 7 June 1996     

Can Sensitized Lymphocytes Retain Reactivity to Inner Ear Antigens After Retrieval From Frozen Storage?

Immune inner ear disease results in rapidly progressive, bilateral sensorineural hearing loss and is one of the few forms of sensorineural hearing loss that can be treated medically. The purpose of this study is to identify and preserve several populations of sensitized lymphocytes from patients with immune inner ear disease as a first step toward cloning autoreactive T cells, in order to study the pathogenesis of disease. Lymphocytes from four patients with high reactivity (stimulation index of 2.5 or greater) were placed in frozen storage. At 8 to 14 months they were thawed and restimulated. All four samples were viable. Two reacted again to inner ear homogenate, but with different intensities. Some lymphocytes sensitized to inner ear antigens can retain reactivity after frozen storage. This methodology may be useful to clone highly reactive T cells.     

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.     

Suppression of luteal phase, but not midcycle, prolactin levels by chronic follicular phase opiate antagonism

Objective: To investigate whether establishment and maintenance of chronic opioid blockade throughout the follicular phase of the menstrual cycle influences midcycle and luteal phase prolactin levels.Design: Randomized, double-blind, crossover study.Setting: Academic research environment.Patient(s): Volunteers, aged 21–35 years, with regular menstrual cycles.Intervention(s): Naltrexone (50 mg) or placebo were administered on cycle days 2–14. Blood samples were obtained in the early follicular phase and in the periovulatory and midluteal phases of the menstrual cycle.Main Outcome Measure(s): Serum prolactin levels.Result(s): In the early follicular phase, serum prolactin levels were equivalent in naltrexone (12.0 ± 2.7 μg/L; mean ± SE) and placebo (12.1 ± 2.9 ug/L) cycles. A statistically significant increase in serum prolactin was observed on the day of the LH surge (naltrexone: 22.6 ± 3.7 μg/L; placebo: 21.7 ± 2.7 μg/L; P < 0.05 versus early follicular phase), but no difference between treatments was observed. However, midluteal prolactin levels were statistically significantly lower in naltrexone cycles compared with placebo cycles (12.6 ± 3.3 versus 15.4 ± 3.0 )ug/L; P < 0.05).Conclusion(s): Chronic blockade of opioid activities during the follicular phase does not affect midcycle prolactin increments, but withdrawal of opioid blockade may enhance opioid effects on prolactin levels in the luteal phase.     

Dietary factors and cancers of breast, endometrium, and ovary: Strategies for modifying fat intake in African American women

Modification of dietary fat and fiber could help prevent cancers of the breast, endometrium, and ovary that are prevalent in African-American women. Dietary intervention programs aimed at reducing fat intake have had mixed results in this population. The transtheoretic model is proposed for achieving dietary change. Strategies for changing health behaviors in African-American women include heightening sensitivity to cultural values among health educators and the use of multiple strategies to reinforce messages. To stimulate healthier eating, it is important to incorporate the distinct habitual eating patterns into innovative intervention methods, using effective behavioral change methods. (Am J Obstet Gynecol 1997;176:S255-64.)     

Primary Endodermal Sinus Tumor of the Vulva: A Case Report and Review of the Literature

Background.Extragonadal endodermal sinus tumors arising in the external genitalia represent an exceedingly rare malignancy in women. Six cases of endodermal sinus tumors of the vulva have been reported to date, with three cases failing to respond to conservative surgery and vincristine-based chemotherapy. We report a seventh case of vulvar endodermal sinus tumor that was treated with radical surgery and platinum-based chemotherapy.Case.RT is an 18-year-old female who presented with a vulvar mass that was diagnosed as endodermal sinus tumor at the time of biopsy. She was subsequently treated with modified radical vulvectomy and ipsilateral groin lymphadenectomy, followed by bleomycin, etoposide, and cisplatin chemotherapeutic regimen. She has since remained free of disease for 18 months as evidenced by serum α-fetoprotein and physical exam at 18 months.Conclusions.Vulvar endodermal sinus tumors represent a very small number of germ cell tumors in women. Based on the previous accounts, this disease appears to be more fatal than endodermal sinus tumor arising at other sites. These tumors also have a predilection for local metastasis. Due to the previous accounts, we chose to treat this patient with radical surgery and platinum-based chemotherapy. This treatment regimen has resulted in a disease-free state for 18 months.     

Direct gamete uterine transfer in patients with tubal absence or occlusion

Purpose: Our aim was to examine the potential of the uterine cavity to affect fertilization and early embryo development. Design: A prospective IRB-approved protocol for patients fulfilling study eligibility criteria was used. Methods: Patients studied included those with primary or secondary infertility, aged less than 38 years, with no history of severe male-factor infertility, and with hysterosalpingogram-and laparoscopic-confirmed bilateral proximal tubal occlusion. Superovulation induction was accomplished with a combination of GnRH agonist and menotropins, with serum hormonal and sonographic monitoring. Within 24 hr prior to, and again at the time of, ovulatory hCG administration, progesterone (P4) was given. Sonographic-guided transvaginal retrieval was performed 35 hr after hCG. Between four and six oocytes were returned to the uterine cavity, admixed with sperm, immediately following retrieval. Luteal support consisted of daily P4 administration. Results: Of the 20 patients recruited for the study, all completed the retrieval and transfer procedure. A total of four clinical pregnancies was achieved, with one early first-trimester loss, one late first-trimester loss (Trisomy 14), and two healthy term infants delivered. IVF of surplus oocytes demonstrated a 82.5% fertilization rate and 66.7% cleavage following cryopreservation. Conclusions: Human fertilization can be achieved through direct uterine transfer of gametes. Furthermore, administration of P4 prior to the ovulatory dose of hCG is compatible with in vitro or in vivo fertilization and implantation.     

A randomized controlled trial of a new fetal acoustic stimulation test for fetal well-being

OBJECTIVES: Our purpose was to determine (1) whether a fetal acoustic stimulation test results in more palpable fetal movement compared with a mock test (control) and (2) whether palpated fetal movements after a fetal acoustic stimulation test are accompanied by a reactive nonstress test.STUDY DESIGN: In a randomized controlled trial we studied women seen in the labor and delivery suite for various indications. Women were excluded for multiple gestation, <31 weeks' gestational age, treatment with magnesium sulfate or narcotics, or ruptured membranes. Informed consent was obtained from eligible women, who were then randomized to a test or control group. We placed an acoustic stimulator on the abdomen of each woman, but only the test group was stimulated. We assessed fetal movement by a grading system: 0 = no fetal movement felt by patient or tester, 1 = fetal movement felt by patient only, 2 = fetal movement felt by tester, 3 = visual movement seen by tester. A positive fetal acoustic stimulation test result was defined as one with any fetal movement felt or seen by the tester (grades 2 or 3). We then performed a nonstress test. We compared rates of a positive fetal acoustic stimulation test in the test and control groups with the χ² test. A p value <0.05 was considered significant.RESULTS: We randomized 297 women to the test group and 280 women to the control (mock test) group. Of women tested with the fetal acoustic stimulation test, 81% had fetal movement by palpation or visualization (grades 2 or 3) compared with 19% of the control group (p < 0.0001, odds ratio 19.29, 95% confidence interval 12.42 to 30.07). Of the test group, 283 (95%) had a reactive nonstress test and 14 (5%) had nonreactive tests; the control group had 267 (95%) reactive and 13 (5%) nonreactive nonstress tests. Of 242 patients in the test group with a positive fetal acoustic stimulation test, 236 (98%) had a reactive nonstress test. Of those in the test group with fewer than three contractions per 10 minutes, 164 (89%) had a positive fetal acoustic stimulation test. Of these, 162 (99%) had a reactive nonstress test.CONCLUSION: The fetal acoustic stimulation test evokes significantly more palpated or visualized fetal movement than in controls. Palpated or visualized fetal movement after acoustic stimulation was almost always accompanied by a reactive nonstress test. (Am J Obstet Gynecol 1997;176:1386-8.)