Soil water repellency induced by long-term irrigation with treated sewage effluent.

This study describes soil water repellency developed under prolonged irrigation with treated sewage effluent in a semiarid environment. Soil surface layer (0-5 cm) and soil profile (0-50 cm) transects were sampled at a high resolution at the close of the irrigation season and rainy winter season. Samples from 0- to 5-cm transects were subdivided into 1-cm slices to obtain fine scale resolution of repellency and organic matter distribution. Extreme to severe soil water repellency in the 0- to 5-cm soil surface layer persisted throughout the 2-yr study period in the effluent-irrigated Shamouti orange [Citrus sinensis (L.) Osbeck cv. Shamouti] orchard plot. Nearby Shamouti orange plots irrigated with tap water were either nonrepellent or only somewhat repellent. Repellency was very variable spatially and with depth, appearing in vertically oriented "repellency tongues." Temporal and spatial variability in repellency in the uppermost 5-cm soil surface layer was not related to seasonality, soil moisture content, or soil organic matter content. Nonuniform distribution of soil moisture and fingered flow were observed in the soil profile after both seasons, demonstrating that the repellent layer had a persistent effect on water flow in the soil profile. A lack of correlation between bulk density and volumetric water content in the soil profile demonstrates that the observed nonuniform spatial distribution of moisture results from preferential flow and not heterogeneity in soil properties. Soil water repellency can adversely affect agricultural production, cause contamination of underlying ground water resources, and result in excessive runoff and soil erosion.

BRCA1 germline mutation presenting as an adenocarcinoma of unknown primary.

BACKGROUND: The work-up of adenocarcinoma of unknown primary usually includes history, physical examination, radiographic imaging, tumor markers, and more recently molecular and genetic information. We report here on how the suggestion by family history of a BRCA1 mutation guided the diagnostic and therapeutic approach in a patient with metastatic carcinoma of unknown primary. METHODS: BRCA1 mutation was screened for by polymerase chain reaction (PCR) and single-strand conformational polymorphism analysis. Primers for PCR amplification included selected BRCA1 exons 2, 110, 11L, 13, and 20. The PCR product was cloned into a PCRII vector and sequenced with a Sequenase Version 2.0 Sequencing Kit. RESULTS: Single-strand conformational polymorphism analysis suggested a mutation in the region of exon 20 and sequencing confirmed the presence of a germline mutation 5382insC. CONCLUSIONS: This case illustrates an unusual presentation of adenocarcinoma of unknown primary in a patient with a germline BRCA1 mutation, the use of a suspected germline mutation to guide the work-up and treatment, and finally the value of positron emission tomography scanning in the work-up of an unknown primary.

Xanthogranulomatous tubo-ovarian abscess resulting from chronic diverticulitis.

We report a case of xanthogranulomatous tubo-ovarian abscess which was preoperatively suspected to be an adnexal neoplasm. With foreign body material found in the abscess wall and vegetable fiber in the tubal lumen, a previously treated chronic diverticulitis was the presumed cause. Culture studies showed polymicrobial isolates which included Escherichia coli, an enteric pathogen. After surgery, administration of antibiotics, and revision of delayed subcutaneous wound healing, the patient is reportedly well.

Activity and pharmacodynamics of 21-Day topotecan infusion in patients with ovarian cancer previously treated with platinum-based chemotherapy. New York Gynecologic Oncology Group.

PURPOSE: Twenty-one-day topotecan infusion was administered as second-line therapy in patients with previously treated ovarian cancer (based on our prior favorable phase I experience) to determine its activity, time to progression, and pharmacodynamics. PATIENTS AND METHODS: Ovarian cancer patients with measurable lesions and one prior platinum-containing regimen were eligible. Topotecan 0.4 mg/m(2)/d 21-day continuous ambulatory intravenous infusion, with appropriate dose modifications for toxicity, was administered every 28 days. Weekly blood levels of topotecan and topoisomerase-1 (topo-1) levels in peripheral-blood mononuclear cells (PBMCs) were determined for pharmacodynamic correlation. RESULTS: Twenty-four patients were entered onto the study (six cisplatin-refractory, five relapsing within < 6 months and 13 relapsing > 6 months after platinum-based therapy). A total of 128 cycles of topotecan (median, four cycles per patient; range, one to 12 cycles) were administered. The major toxicity was neutropenia (29% grade 3 in all cycles and 4% grade 4). One episode of grade 4 thrombocytopenia (4%) occurred. Fifty-two percent of the patients had anemia that required transfusions. Eight of 23 patients with measurable disease (35%; 95% confidence interval [CI], 15% to 54%) had partial responses (PRs) lasting longer than 1 month. Two of these patients had minor residual computed tomographic changes but had clinical complete remissions that lasted up to 53 weeks while they were not undergoing further therapy. One patient with nonmeasurable disease had a PR (by CA-125 criteria) that lasted 6 months, for an overall response rate of 38% in nine of 24 patients (95% CI, 18% to 57%). The median time to progression was 26 weeks. Pharmacodynamic analysis demonstrated a statistically significant decrease in free PBMC topo-1 level at weeks 2 and 3 of drug administration. There was a strong statistical correlation between the decrease in free topo-1 levels and increasing area under the curve (AUC) for topotecan. This was confirmed in a pharmacodynamic model. CONCLUSION: Twenty-one-day infusion is a well-tolerated method of administering topotecan. Pharmacodynamic studies demonstrate correlations between (1) the week of infusion and the PBMC topo-1 level, (2) the AUC of topotecan and the decrease in topo-1 levels, and (3) the change in topo-1 level and the neutrophil nadir. The objective response rate of 35% to 38% (95% CI, 15% to 57%) in this small multicenter study is at the upper level for topotecan therapy in previously treated ovarian cancer. Prolonged topotecan administration therefore warrants further investigation in larger, randomized studies comparing this 21-day schedule with the once-daily-for-5-days schedule.

A phase II double-blind randomized study of the simultaneous administration of recombinant human interleukin-6 and recombinant human granulocyte colony-stimulating factor following paclitaxel and carboplatin chemotherapy in patients with advanced epithelial ovarian cancer.

PURPOSE: Recombinant human interleukin-6 (rhuIL-6) is a glycosylated cytokine with hematopoietic stimulatory effects. In particular, preclinical studies suggest the agent can stimulate thrombopoiesis, even in conjunction with chemotherapy. We attempted to determine whether higher dose chemotherapy for ovarian cancer was possible given the pharmacologic use of this important growth factor. METHODS: We conducted a randomized, double-blind phase II study of IL-6 plus granulocyte colony-stimulating factor (G-CSF) versus placebo plus G-CSF in combination with a standard chemotherapy regimen. Patients with epithelial ovarian cancer, stages Ic to IV, were eligible. All patients were previously untreated with chemotherapy and had Karnofsky performance status >/=60. rhuIL-6 (Escherichia coli, SDZ ILS 969) 1.0 micrograms/kg or placebo was given subcutaneously on days 2-8 every cycle together with G-CSF 5.0 micrograms/kg subcutaneously days 2-15, following administration of paclitaxel 175 mg/m2 as a 3-h infusion and carboplatin given to a desired AUC of 7.5 on day 1 every 21 days. RESULTS: Fifty patients were entered in this study, although the study was temporarily suspended by the FDA in midstudy over manufacturing concerns. Therefore, 37 patients were evaluable for efficacy of growth factor; 19 patients received placebo plus G-CSF and 18 rhIL-6 plus G-CSF. There was no difference in prognostic variables between these two groups. Platelet nadirs were lower in the first cycle for the placebo group (P = 0.004, Wilcoxon sum-rank test) but not in other cycles. There was no statistically significant difference in cycle treatment delays, carboplatin dose delivered, number of patients with grade 4 thrombocytopenia, or platelet transfusion. Nonetheless, the trend of the data favored IL-6 in all cases. CONCLUSIONS: This study demonstrated a minimal effect (statistically significant in the first cycle only) on thrombopoiesis in women undergoing paclitaxel and carboplatin therapy of ovarian cancer. No clinically significant effect on actual chemotherapy delivery was demonstrated, however. Future studies, if warranted, to ameliorate thrombocytopenia should be carried out with regimens producing even greater thrombocytopenia than the current regimen in the control arm.

All-trans retinoic acid and interferon-alpha-2a in patients with metastatic or recurrent carcinoma of the uterine cervix: clinical and pharmacokinetic studies. New York Gynecologic Oncology Group.

BACKGROUND: Recent clinical trials with a combination of interferon (IFN alpha) and 13 cis-retinoic acid resulted in high response rates among women with locally advanced and metastatic carcinoma of the uterine cervix. The authors sought to amplify these observations by employing the isomer of 13 cis-retinoic acid, all-trans retinoic acid (tRA), in combination with IFN alpha. METHODS: Sequential clinical trials were initiated by the New York Gynecologic Oncology Group to test the combination of tRA and IFN alpha in women with metastatic or recurrent carcinoma of the cervix who had failed primary therapy. IFN alpha was administered at 6 MU subcutaneously 3 times per week. In the first trial, tRA was administered at 50 mg/m2 orally 3 times per day on a daily schedule (daily regimen), whereas in the second trial, tRA was administered at the same dose 3 times per day, but only on Days 1-3 each week (intermittent schedule). Clinical outcomes included response to therapy and survival. Plasma pharmacokinetic studies of tRA were performed in both trials to assess the effects of different schedules on plasma levels of the drug. RESULTS: Fourteen women with metastatic or recurrent squamous cell carcinoma of the cervix were enrolled in the daily trial and 12 women in the intermittent trial. There was no clinical activity for either regimen, and both studies were terminated according to an early stopping rule. Because tRA has been reported to induce its own metabolism, plasma levels of tRA were measured on Days 1, 8, and 28. The change in the area under the time versus tRA concentration curve (AUC) was significantly different between the two groups. The average AUC on Day 8 was 14% of that observed on Day 1 for the daily treatment group; in contrast, it was 107% on Day 1 in the intermittent treatment group. In 6 of 8 patients studied in the daily trial, the AUC decreased at least 60% by either Week 2 or Week 4. In contrast, in the intermittent trial, only 3 of 9 patients experienced >60% decrease in plasma levels of the drug at either Day 8 or Day 28. CONCLUSIONS: The combination of tRA + IFN alpha was inactive in patients with advanced carcinoma of the cervix when employed at these doses on either the daily or intermittent schedule. The failure of activity of this regimen did not result from induction of metabolism of tRA, suggesting that intrinsic mechanisms of resistance to tRA at the cellular level may be of greater importance.

Coexistent atypical polypoid adenomyoma and endometrial adenocarcinoma.

Atypical polypoid adenomyoma (APA) is a rare entity that is believed to follow a benign course. We report a case of APA with coexistent endometrial adenocarcinoma. The example raises the possibility that APA may progress to endometrial adenocarcinoma in some cases.

A phase I trial of cyclosphosphamide and carboplatinum combined with interleukin-3 in women with advanced-stage ovarian cancer.

The hematopoietic growth factor, recombinant human interleukin-3 (rhu IL-3), stimulates production of both leukocytes and platelets, and thus potentially has greater utility than growth factors that solely stimulate leukocytes production when employed with dose-intensive chemotherapeutic regimens. To determine the optimal schedule for administration of rhu IL-3 in combination with cyclophosphamide and carboplatin, an aggressive regimen for the treatment of advanced ovarian cancer, a phase I trial was initiated by the New York Gynecologic Oncology Group. Following surgical debulking, all patients received cyclophosphamide and carboplatin for 6 cycles. rhu IL-3 was administered at 50, 250, or 500 microgram subcutaneously for 5 days either immediately prior to or after administration of chemotherapy. Cohorts of six patients were treated at each dose level (three pre- and three postchemotherapy). Eighteen patients received 91 cycles of treatment. The major toxicities attributable to rhu IL-3 included fevers, chills, malaise, nausea, and headache, but were not dose-limiting at the doses of rhu IL-3 employed. The major finding of this study was that rhu IL-3 administered after chemotherapy offered greater platelet protection than rhu IL-3 administered prior to chemotherapy as assessed by median platelet nadir and duration of platelet counts < 50,000/mm3. A second major finding was a dose-response relationship for rhu IL-3: the two higher doses employed, 250 and 500 micrograms, offered more effective platelet protection than the lower dose employed, 50 micrograms. rhu IL-3 had no significant effects on leukocyte nadirs or duration of nadirs at any schedule or dose employed. rhu IL-3 may reduced the thrombocytopenia associated with aggressive treatment with cyclophosphamide and carboplatin, although this remains to be confirmed in a randomized, placebo-controlled trial. The effects of rhu IL-3 are dose- and schedule-dependent.

Successful implementation of a guideline program for the rational use of lipid-lowering drugs.

Following the National Cholesterol Educational Program's (NCEP) 1988 screening and treatment recommendations, an educational and behavior-change program at Group Health Cooperative of Puget Sound (GHC) was developed to guide the use of lipid-lowering drugs within the larger context of cardiac risk reduction. The program has been successful in advancing a rational program to enhance care and manage costs of the use of lipid-lowering agents at GHC. Cost savings have been significant over the past two years. The educational design of the program includes training and ongoing education of a core group of "lipid gurus," who educate colleagues in area medical centers in a rational approach to hyperlipidemia. Patient education and patient participation in decision-making was emphasized. Program evaluation has demonstrated that physicians and patients are satisfied with the program, and inappropriate drug expenditures have been prevented. Key elements of the program include a critical review of outcome studies in the medical literature, use of information systems, algorithms and written materials organized into a well-designed, ongoing educational program, and development of a core group of physicians and pharmacists to administer the program at the clinic level.

Hexamethylmelamine for the treatment of ovarian cancer--the Mount Sinai experience.

Two regimens were tested, CHAP I and CHAP II, the latter, a hexamethylmelamine dosage-intensive regimen, first as second line (salvage) therapy and then as primary therapy. Both produced the most successful results achieved in the Mount Sinai series up to the time of their introduction, when compared to their predecessor regimens: CAP, AP and P. In an overall interim comparison, CHAP II was significantly superior to historical AP and CAP as primary therapy, as was CHAP I vs. AP in several important subgroups compared as part of a randomized trial. CHAP II overall progression-free survival was improved in spite of added new sensitive test methods. Salvage therapy also improved markedly with the addition of intensive hexamethylmelamine. Several biological and treatment characteristics strongly influenced outcome, especially young age and adding hexamethylmelamine. Other possible factors included: poor tumor grade, poor performance status, and extent of surgical debulking, even to intermediate residual, 2-6 cm size [CHAP II only]; extensive (optimum) surgery [CHAP I only]. The hexamethylmelamine-containing regimens interact favorably with some of these factors, better than did the preceding regimens. Five-year follow-up analyses weakened slightly for extensive surgery, intermediate size and poorly differentiated tumors. It confirmed and strengthened several findings favoring CHAP I & II, the hexamethylmelamine-containing regimens.

Endometrioid carcinoma of the fallopian tube: pathology and clinical outcome.

A case of endometrioid carcinoma of the fallopian tube is reported with histologic description and clinical follow-up of four years. Only two other cases have been documented previously. This case is thought to be unique as the carcinoma arose in a benign endometrioid tumor. Inferences concerning Mullerian duct expression and neoplasia are reviewed.

Responsiveness of L-S ratio of the amniotic fluid to intra-amniotic administration of thyroxine. Role of fetal age.

Since 1982 we have accelerated fetal maturation with intra-amniotic thyroxine (T4) in more than 140 patients. The purpose of this analysis was to determine the rate of change of the ratio of lecithin to sphingomyelin (L/S) after administration of T4 at different gestational ages, and to compare the responses to the first and the second administration of T4. Fifty-nine cases in which administration of T4 was continued for 2 weeks or more, and in which at least 3 determinations of L/S had been performed, were identified. Gestational age of the fetus at the inititiation of treatment ranged from 26 to 31 weeks (mean 29.3 weeks). Thyroxine was administered weekly in 200 to 500 mcg doses. Administration of T4 prior to the 27th week did not change the L/S. From the 27th and 31st week of gestation, the slope of the L/S, after the initial dose of T4 increased from 0.33/wk to 1.05/wk. In contrast the slope of the untreated patients changed little reaching a maximum of 0.22 at the 33 week. L/S greater than 2 was observed in 80% of cases after 2 weeks of therapy, when it had been initiated after the 26th week. The response to the second dose was about twice that of the first in fetuses less than or equal to 30 weeks, but was similar to that seen after the initial dose in fetuses greater than 30 weeks. Phosphatidylglycerol (PG) was detected in amniotic fluid in 51% of cases after 2 weeks of treatment, and in 6 instances as early as at the 30th week. Responsiveness of L/S to T4 treatment of the fetus is a function of gestational age and of prior exposure to T4.

Acceleration of fetal maturation with intra-amniotic thyroxine in the presence of maternal malignancy.

Acceleration of fetal maturation with intra-amniotic administration of thyroxine was employed in eight patients in whom preterm delivery was necessary because of malignant disease of the mother. Thyroxine (200 mcg to 500 mcg) was given at weekly intervals starting at the 27th to 32nd week of gestation until the L-S ratio exceeded 2.0. The fetuses were delivered between the 29.4 and 34.0 week. None of the newborns suffered from respiratory distress syndrome, and three newborns were cared for in the regular nursery. Thyroxine-induced acceleration of fetal maturation and pre-term delivery permits earlier initiation of antineoplastic and radiation therapy without exposing the fetus to the hazards of maternal therapy and those of prematurity.

Single cause for initiation of labor and toxemia: a hypothesis.

A hypothesis is presented that states that the decline in oxygen tension (PO2) in the intervillous space causes both toxemia (preeclampsia-eclampsia) and the initiation of labor. The trophoblast is identified as the monitor of the fetal PO2 and as the source of substances that are released into the maternal circulation stimulating the myometrium, the heart, the vascular smooth muscle, and, perhaps, the brain. In the presence of normal trophoblast the release takes place only when the PO2 in the intervillous space decreases to a level at which the fetus should be expelled from the uterus to avoid intrapartum hypoxia. Near term, the myometrium is the most responsive site to the released substances, and stimulation of the heart and systemic vasculature is observed only infrequently. With release of these substances, intrapartum toxemia results. Toxemia before onset of labor is created by hypoxia of the trophoblast in the presence of a nonresponsive myometrium to materials released. A small placenta, compression of the intervillous space by villous edema, and avulsion of spiral arterioles are the main causes of the premature decline of intervillous space PO2, leading to toxemia. Postpartum toxemia is produced by the retained (extraplacental) trophoblast, perhaps facilitated by the rapid clearance of progesterone.