Impact of manure phosphorus fractions on phosphorus loss from manured soils after incubation.

The risk of P loss from manured soils is more related to P fractions than total P concentration in manure. This study examined the impact of manure P fractions on P losses from liquid swine manure- (LSM), solid cattle manure- (SCM), and monoammonium phosphate- (MAP) treated soils. Manure or fertilizer was applied at 50 mg P kg soil, mixed, and incubated at 20°C for 6 wk to simulate the interaction between applied P and soil when P is applied well in advance of a high risk period for runoff. Phosphorus fractions in manure were determined using the modified Hedley fractionation scheme. We used simulated rainfall (75 mm h⁻¹ for 1 h) to quantify P losses in runoff from two soils (sand and clay loam). The proportion of total labile P (total P in water+NaHCO fractions) in manure was significantly greater in LSM (70%) than SCM (44%). Mean dissolved reactive P (DRP) load in runoff over 60 min was greatest from MAP-treated soil (18.1 mg tray⁻¹), followed by LSM- (14.0 mg tray⁻¹) and SCM- (11.0 mg tray⁻¹) treated soils, all of which were greater than mean DRP load from the check (5.2 mg tray⁻¹). Total labile P (water+NaHCO) in manure was a more accurate predictor of runoff DRP loads than water extractable P, alone, for these two soils. Therefore, NaHCO extraction of manure P may be a useful tool for managing the risk of manure P runoff losses when manure is applied outside a high risk period for runoff loss.

Role and mechanism of action of tamoxifen in premenopausal women with metastatic breast carcinoma.

Tamoxifen was evaluated as initial hormone therapy for metastatic breast cancer in 85 premenopausal patients. Tamoxifen responders continued on tamoxifen, while tamoxifen failures and initial responders who later progressed were to receive ovarian ablation next. Of 74 evaluable patients, 5 had complete responses (CR) and 15 had partial responses (PR) while 12 remained stable (ST), giving response rates of 27% (CR + PR) or 43% (CR + PR + ST). Of the 23 patients who initially responded (CR + PR + ST) to tamoxifen but then progressed and received ovarian ablation alone, 15 are assessable. Nine (60%) responded (CR + PR + ST) to ovarian ablation. Sixteen patients who failed tamoxifen had ovarian ablation alone, and of 14 assessable patients 2 had ST while 12 progressed. Thus response to tamoxifen strongly predicted response to ovarian ablation (P = 0.021). Serial follicle stimulating hormone, prolactin, and estradiol levels suggested that tamoxifen does not act by induction of a "medical ovariectomy" or by alteration of prolactin levels in premenopausal patients.

Significance of a partial or slow response to front-line chemotherapy in the management of intermediate-grade or high-grade non-Hodgkin's lymphoma: a literature review.

PURPOSE: The purpose of this review was to assess the outcome of patients with non-Hodgkin's lymphoma (NHL) who achieve an incomplete or slow response to front-line chemotherapy and to determine whether salvage treatment with intensive combination chemotherapy with or without autologous bone marrow transplantation (ABMT) is successful in such patients. METHODS: A comprehensive literature search of studies using combination chemotherapy for the front-line therapy of advanced-stage intermediate- and high-grade NHL and for salvage therapy of patients with a partial response (PR) was reviewed. RESULTS: The median survival duration of patients with a PR ranged between 5 to 14 months, while the median survival duration of patients with a complete response (CR) was not reached in many studies. For patients in CR, the probability of survival at 24 months ranged between 0.79 to 1, while for patients in PR it ranged from 0 to 0.31. The rapidity of a response to front-line therapy was often found to be of prognostic importance. Patients who relapsed after a PR to front-line therapy had similar outcomes to intensive salvage therapy as those who relapsed after a CR. ABMT performed immediately after a PR to induction therapy, before progressive disease occurred, resulted in high CR rates in nonrandomized studies. CONCLUSION: Patients with aggressive NHL who experience a PR or who respond slowly to front-line chemotherapy have a poor prognosis. Early introduction of dose-intensive salvage therapy before the development of progressive disease may benefit patients with a PR and requires testing in randomized clinical trials.

Hormone replacement therapy in women with breast cancer. Do the risks outweigh the benefits?

PURPOSE: To review critically the literature regarding effects of estrogen replacement therapy (ERT)/combined estrogen and progesterone replacement therapy (HRT) on the risk of breast cancer and on other health risks and benefits in postmenopausal women, with a focus on risks and benefits in women with a previous diagnosis of breast cancer. METHOD: A literature search was conducted using Medline, Cancerline, and the bibliographies of reports published as of March 1995. All five published meta-analyses that examined the risk of breast cancer in relation to ERT/HRT in otherwise healthy women were critically reviewed. All known reports of women with a history of breast cancer given ERT/HRT subsequent to diagnosis and additional reports regarding the benefits of ERT/HRT were also reviewed. RESULTS: None of the five meta-analyses demonstrated a significantly increased risk of developing breast cancer in ever users compared with never users of ERT/HRT. Current use may be associated with a small increased risk. This increased risk should be balanced by the expected benefits of ERT/HRT on quality of life, bone metabolism, and cardiovascular function. Preliminary information does not suggest a major detrimental effect of ERT/HRT in women with a previous diagnosis of breast cancer, but these reports include few women with limited follow-up data. There are no randomized trials in women with a previous diagnosis of breast cancer. CONCLUSION: In healthy postmenopausal women, the benefits associated with ERT/HRT outweigh the risks. In women with a previous diagnosis of breast cancer, the balance of risks and benefits should be explored in randomized controlled trials.

Detection of occult lymphoma in the peripheral blood and bone marrow of patients with untreated early-stage and advanced-stage follicular lymphoma.

PURPOSE: The object of this study was to compare the relative sensitivities of morphologic, immunophenotypic, gene rearrangement, cytogenetic, and polymerase chain reaction (PCR) analyses in the detection of lymphoma cells in the bone marrow and peripheral blood of patients with follicular lymphoma. PATIENTS AND METHODS: Bone marrow and peripheral-blood samples from 28 newly diagnosed patients with follicular lymphoma referred from several different medical centers were assessed. Routine morphologic assessment was performed initially and the remainder of the sample was aliquoted for DNA extraction to be used for gene rearrangement and PCR analyses and for immunophenotypic and cytogenetic analyses where a sufficient amount of sample remained. RESULTS: Morphologic assessment of the bone marrow was positive for lymphoma cells in 11 of 28 patients. PCR amplification of t(14;18) breakpoint DNA detected lymphoma cells in 17 of 24 patients assessed. Morphologic assessment detected lymphoma cells in three bone marrow samples that were negative by PCR. PCR analysis was the only method able to detect circulating lymphoma cells in peripheral blood at diagnosis and was positive in 15 of 24 samples. The other methods of assessment did not show lymphoma in any samples in which lymphoma was not detected by morphologic or PCR analysis. Lymphoma cells were found in the bone marrow and/or peripheral blood as frequently in early-stage patients as in advanced-stage patients. CONCLUSION: PCR amplification of t(14;18) breakpoint DNA together with morphologic assessment had the highest yield of detecting lymphoma cells in the bone marrow and/or peripheral blood of our population of newly diagnosed patients with follicular lymphoma. The clinical significance and prognostic importance of lymphoma cells detected by PCR in the bone marrow and/or peripheral blood of newly diagnosed follicular lymphoma patients awaits long-term follow-up data of these and additional patients.

Appropriateness of adjuvant systemic therapy for axillary node-negative breast cancer: a physician opinion survey.

PURPOSE: To examine variations in physicians' recommendations for systemic adjuvant therapy in the treatment of women with node-negative breast cancer (NNBC) and to determine factors used in making specific recommendations. MATERIALS AND METHODS: A questionnaire was sent by mail to all 149 Ontario physicians who actively treated breast cancer in 1993. The questionnaire described 48 clinical scenarios of women with NNBC, which included all possible combinations of the following factors: menopausal status, tumor size, hormone receptor status, histologic and nuclear grade, and lymphatic and/or vascular invasion. Respondents rated the appropriateness of administering tamoxifen, combination chemotherapy, or both tamoxifen and combination chemotherapy on a nine-point scale from extremely inappropriate to extremely appropriate. Respondent agreement and disagreement were tabulated for each scenario, and factors associated with specific treatment ratings were analyzed by logistic regression. RESULTS: The response rate was 87%. Agreement for the appropriateness of specific therapies was most evident where clinical trials have demonstrated efficacy, whereas disagreement was observed in scenarios in which support for a specific treatment is not available in the current literature. Relevant tumor- and patient-specific factors were used in decision-making; personal characteristics of the respondents had no statistically significant impact on appropriateness ratings. CONCLUSION: The physicians surveyed had good knowledge of NNBC prognostic factors, but had a range of opinion on optimal therapy for many clinical scenarios, which reflects current knowledge of the benefits of adjuvant therapy for NNBC.

Sequence preservation of the third exon of the bcl-2 gene in non-Hodgkin's lymphoma: absence of somatic hypermutation.

The t(14;18) translocation juxtaposes the bcl-2 gene on chromosome 18 to a joining (J) gene segment of the immunoglobulin heavy chain gene (IgH) on chromosome 14. Up to 85% of non-Hodgkin's lymphomas (NHL) are t(14;18) positive. Recent reports have documented point mutations in the second exon of translocated bcl-2 alleles and postulated that immunoglobulin variable (V) region somatic hypermutation, related to Ig sequences approximately 250 Kb downstream, may be mediating these mutations. We have examined the third exon of bcl-2, directly adjacent to Ig sequences in the t(14;18), for point mutations. In particular, we studied the translated region of exon 3 in 45 NHLs by SSCP analysis and failed to detect a single point mutation. Further, we sequenced eleven t(14;18) breakpoints, including both bcl-2 and JH sequences, and detected only one point mutation, in a JH-derived sequence. We conclude that immunoglobulin V region somatic hypermutation does not induce point mutations into the t(14;18) breakpoint region or into the translated region of the third exon of bcl-2 alleles involved in the t(14;18) translocation, conserving the membrane insertion properties of the carboxyl tail of this protein.

An improved statistical approach: can it clarify the role of new prognostic factors for breast cancer?

Recently, there has been a proliferation of new biomarkers, some of which may lead to an improved prognostic index or may influence treatment selection. However, there are methodological and statistical issues that require attention in assessing the role and use of these prognostic factors. Between 1977 and 1986, 1097 primary breast cancer patients were accrued for multidisciplinary research at the Henrietta Banting Breast Centre, Women's College Hospital; follow-up to 1990 is complete for 96% of the patients. Data for these patients are used here to illustrate strategies: (1) for the comparison of results from diverse assessments of biomarkers; (2) for the improved comparability of inter-laboratory results; (3) for the examination of the results from monoclonal or polyclonal antibody assays for possible clinically relevant bimodality; (4) for good statistical resolution of overlapping distributions; (5) that involve the use of quantitative values for prognostic factors whenever possible; and (6) for improved multivariate analyses. Good data handling and analyses may enable more accurate and rapid assessment of new prognostic factors, thereby expediting and improving their clinical application.

The Henrietta Banting Breast Centre database: a model for clinical research utilizing a hospital-based inception cohort.

The cohort study design has been used successfully in clinical cancer research. Cohorts, however, are valuable only if they produce results which are valid and generalizable. Some hospital-based inception cohorts satisfy both these requirements and may thus be useful research tools. The development of one such hospital-based cohort, the Henrietta Banting Breast Centre database, is described. This cohort is composed of 1097 women diagnosed with primary breast cancer at Women's College Hospital, Toronto, from January 1977 through December 1986. Details of diagnostic procedures, pathology, treatment, dates and sites of recurrence, and date of death are available on 96% of women. By comparison with published series and with the Ontario Cancer Registry, we have demonstrated validity and generalizability. A major advantage is the ready availability of paraffin tissue blocks on virtually all cases, facilitating analyses of the prognostic importance of specific biologic variables and immunocytochemical hormone assays. Other completed studies and future uses of the cohort are described.

An investigation of cut-points for primary breast cancer oestrogen and progesterone receptor assays.

Oestrogen and progesterone receptor (ER and PgR) assay values are frequently used in medical decision-making for breast cancer patients. We have proposed statistical standardization of receptor assay values to improve inter-laboratory comparability, and now report the use of standardized log units (SLU) to investigate the effects of ER and PgR cut-points on time to first recurrence outside the breast (DFS). Between 1980 and 1986, there were 678 primary breast cancer patients treated at the Henrietta Banting Breast Centre (HBBC). The effects of ER and PgR cut-points were examined with multivariate analyses considering the variables: age, tumour size, nodal status, weight and adjuvant treatment. We considered receptor assay cut-points ranging from - 1.0 to + 1.0 SLU (ER between 7 and 166 fmol/mg protein; PgR between 7 and 181 fmol/mg protein). PgR was included in the multivariate prognostic models more often than ER, although patients had a better prognosis with both larger ER and PgR values. There was no best cut-point for ER or PgR, and there was strong evidence that ER and PgR should be considered as continuous rather than dichotomous (negative, positive) variables. Patient prognosis should also be more comparable with SLU.

The standardization of estrogen receptors.

Tumour estrogen receptor (ER) status may determine the medical treatment of a patient with breast cancer; yet inter-laboratory results can vary markedly, particularly when absolute cut-offs in fmol/mg cytosol protein are used. The use of standardized log units is proposed to permit greater inter-laboratory comparability. We have assessed the biochemical ER values using the dextran-coated charcoal method with three data sets, two quality control (QC) sets for Ontario laboratories and a data set with values for 184 primary breast cancer patients seen at Women's College Hospital (WCH) between 1985 and 1986. The distributions for all the raw data were skewed toward the lower end of the range; a log transformation improved the symmetry of the distributions. There was marked inter-laboratory variation in the QC data, and standardized log units greatly reduced this variability. The WCH data had similar differentiation by tumour size and nodal status with both the raw data and standardized log units. However, standardized log units provided more consistent evidence of an association between ER and immunohistochemical ERICA. The standardized log units provide quantitative receptor values suitable for multi-centre research, for future work with clinical outcomes, and for the daily management of patients.

Mitoxantrone-DHAP with GM-CSF: an active but myelosuppressive salvage therapy for relapsed/refractory aggressive non-Hodgkin's lymphoma.

This study was designed to evaluate the efficacy and toxicity of dose intensifying DHAP (dexamethasone, cytarabine and cisplatin) salvage chemotherapy by adding mitoxantrone with GM-GSF support in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL). From March 1992 to January 1995, 22 patients with intermediate and high grade (aggressive) NHL refractory or relapsed after adriamycin containing chemotherapy regimens were treated with M-DHAP+GM-CSF, (dexamethasone 40 mg i.v. days 1-4, cisplatin 100 mg/m2 i.v. by continuous infusion over 24 hours on day 1, cytarabine 2 gm/m2, i.v. every 12 hours for 2 doses on day 2, mitoxantrone 10 mg/m2 i.v. on days 3 and 4 and GM-CSF 250-500 microg/m2 s.c. daily beginning day 5 until absolute neutrophil count recovery. Most patients had poor prognostic factors including primary refractory disease (18/22), bulky disease (12/22), elevated LDH (9/22), or bone marrow involvement (8/22). All 22 patients were evaluable. The overall response rate was 41% (CR 23% and PR 18%). There were three toxic deaths, all related to sepsis. Median progression free survival (PFS) and overall survival (OS) rates were 5.2 months and 11.8 months respectively. At the same time of the analysis two patients were alive after high-dose therapy and bone marrow transplant at 34 and 36 months follow-up and two were alive with disease. The maximal acceptable dosage of mitoxantrone was 10 mg/m2 x 2 due to serious hematologic toxicity. Treatment delays and dose reductions compromised delivering the optimal dose intensity of M-DHAP. A poor prognostic group of patients with refractory or recurrent aggressive lymphoma, many of whom were not eligible for high-dose therapy and stem cell transplantation were treated with repeated cycles of dose intensified DHAP with growth factor support. Although M-DHAP had therapeutic activity even in patients considered to have primary refractory disease, myelosuppression was dose limiting and frequently limited the number of cycles. Therefore, if M-DHAP is to be further evaluated, therapeutic results may be improved further by incorporating strategies to reduce myelotoxicity such as the use of growth factors to reduce platelet transfusion requirements or the use of autologous stem cell support after each cycle.

Treatment of AIDS-related non-Hodgkin's lymphoma with a twelve week chemotherapy program.

Current treatment options for acquired-immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphoma (NHL) are unsatisfactory because of excessive toxicity rates and frequent recurrence of lymphoma. In this phase II study, we evaluated a novel 12 week chemotherapy program with respect to feasibility, toxicity and therapeutic results. Thirty HIV-seropositive patients with intermediate grade or small non-cleaved cell NHL received a 12 week program of weekly intravenous and oral chemotherapy consisting of etoposide, adriamycin, cyclophosphamide, bleomycin, vincristine, methotrexate and prednisone as well as biweekly intrathecal cytosine arabinoside. Prophylaxis against Pneumocystis carinii pneumonia (PCP) and candida were given routinely. The overall objective response rate was 73% with 33% complete responders. The time to progression for those stable or responding was 9.4 months. Five of 10 complete responders are well and free of disease 13.2 to 24.5 months from diagnosis. Median survival for the 30 patients was 8.1 months. NHL was the most common cause of death (13/22); opportunistic infection caused only one death (cryptococcal meningitis). Only 1 case of PCP occurred. The major toxicity was neutropenia. In conclusion this regimen resulted in response rates similar to other reports with acceptable toxicity and a very low incidence of PCP. Relapse of NHL remains a major challenge, however, and further studies are needed. Routine PCP prophylaxis should be incorporated into new trials of therapy for AIDS-related NHL.

HIV-associated lymphoma of the gastrointestinal tract: the University of Toronto AIDS-Lymphoma Study Group experience.

We present a retrospective analysis of 31 (30 male) patients with HIV-associated gastrointestinal lymphoma which was undertaken to determine the natural history and response to therapy. Only seven patients had stage I or II lymphoma and 22 had stage IV. Pathology included diffuse large cell (13), immunoblastic (10), and small cell non-cleaved (7). The median age at presentation was 39 years (range 24-59), and the median CD4 count before treatment was 100/microL (range 4-1150). Eighty-seven percent of patients received systemic chemotherapy and significant response was seen in 84% (CR 38%; PR 46%). Hematologic toxicity was high (febrile neutropenia in 44% and dose reductions were required in 81%) and perforation occurred in five patients. Median survival for all patients was 6 months and death was secondary to lymphoma in 61%, treatment toxicity in 10%, other AIDS-related illnesses in 25% and other causes in 4%. Survival was shorter for patients with bone marrow involvement and for those with poor performance status. HIV-associated GI lymphoma has a poor prognosis despite good initial response to chemotherapy and is associated with a higher perforation rate than in HIV negative patients.

Randomized trial of a patient decision aid for choice of surgical treatment for breast cancer.

A decision aid for the surgical treatment of early breast cancer was evaluated in a randomized controlled trial. The decision aid, a tape and workbook, includes explicit presentation of probabilities, photographs and graphics, and a values clarification exercise. Community surgeons were randomized to use the decision aid or a control pamphlet. Patients completed a questionnaire prior to using the decision aid, after reviewing it but prior to surgery, and 6 months after enrollment. There was no difference in anxiety, knowledge, or decisional regret across the 2 groups. There was a nonsignificant trend toward lower decisional conflict in the decision aid group. A subgroup of women who were initially leaning toward mastectomy or were unsure had lower decisional conflict. Although the decision aid had minimal impact on the main study outcomes, a subgroup may have benefited. Such subgroups should be identified, and appropriate decision support interventions should be developed and evaluated.

Phase II study of trimetrexate in recurrent anaplastic glioma. National Cancer Institute of Canada Clinical Trials Group Study.

The National Cancer Institute of Canada Clinical Trials Group conducted a phase II trial of trimetrexate given in a daily x 5 intravenous bolus schedule every 3 weeks in patients with measurable recurrent anaplastic glioma and limited prior treatment. There were no responses in 14 evaluable patients. We conclude that trimetrexate, given as described, is not an active agent in this disease.

The rise of tamoxifen: temporal and geographical trends of tamoxifen use in Ontario.

PURPOSE: To describe the change in use of tamoxifen over time and across countries in Ontario. METHODS: Data from the Ontario Drug Benefit (ODB) plan, Census Canada, and the Ontario Cancer Registry (OCR) were combined and analysed to determine rates of tamoxifen use for females over 65 for each county and the province overall, by year. Rates were analyzed by repeated measures ANOVA to determine significance of changes over time. Consistency of tamoxifen use across counties was determined by the Spearman rank correlation coefficient, and overall variation between counties was described using three statistical techniques: Chi-square analysis, the extremal quotient (EQ), and the systematic component of variation (SCV). RESULTS: The number of one-month tamoxifen prescriptions per incident case of breast cancer rose significantly from 13.51 in 1985 to 20.54 in 1990 (p < 0.001) and to 34.06 in 1992 (p = 0.001). Viewed differently, the number of women over 65 receiving tamoxifen prescriptions per incident case of breast cancer changed from 1.91 in 1985 to 3.14 in 1990 to 4.54 in 1992. Statistically significant variation in the rate of tamoxifen prescribing was demonstrated between Ontario counties in all three years by Chi Squared analysis (p < 0.0001). Both the EQ and the SCV declined from 1985 to 1990, suggesting more uniform prescribing across the province. Little change in overall variation was seen between 1990 and 1992. All counties over time tended to prescribe generic preparations more often and shifted from 10 mg to 20 mg formulations. CONCLUSIONS: The significant increase in the rate of tamoxifen use and trend towards more uniform prescribing across Ontario between 1985 and 1990 coincided with the publication of two important documents outlining the benefits of tamoxifen in early breast cancer. Despite this trend, variation in tamoxifen use between counties remains. There has been little change in uniformity of prescribing since 1990.

The rate of breast-conserving surgery for early breast cancer is not influenced by the surgical strategy of excisional biopsy followed by the definitive procedure.

Increased emphasis on breast conservation and the primacy of the patient's preferences has led to the promotion and increased use of a two-step surgical strategy (definitive operation only after a final tissue diagnosis from a biopsy done on a previous visit) in the treatment of early breast cancer, with the assumption being that this is more conducive to the performance of breast-conserving surgery (BCS). We sought to test this by examining the effect of the surgical strategy (one-step versus two-step) on the operation performed (BCS versus mastectomy). A random sample of women with node-negative breast cancer diagnosed in 1991 in Ontario was drawn from the Ontario Cancer Registry database and matched to the Canadian Institute of Health Information and Ontario Health Insurance Plan databases (n = 643). This provided information on the timing and nature of all surgical procedures performed as well as patient, tumor, hospital, and surgeon characteristics. The surgical strategy was defined as either a one-step procedure (biopsy and definitive surgery performed at the same time) or a two-step procedure (surgical biopsy and pathologic diagnosis, followed by definitive surgery at a later date). The axillary lymph node dissection was used to define the definitive procedure. BCS was employed in 68% of patients, and this did not differ significantly between the one-step and two-step groups (66% versus 70%). Patients with palpable lesions had a significantly lower rate of breast conservation than those with nonpalpable lesions. Other variables associated with a lower rate of BCS were larger tumor size, presence of extensive ductal carcinoma in situ (DCIS), and central or multifocal tumors. The use of a one-step procedure was associated with a patient age of more than 50 years, a palpable mass, tumor size larger than 1 cm, previous fine needle aspiration (FNA) biopsy, absence of extensive DCIS, and surgery in an academic setting. Breast conservation was not affected by the surgical strategy used or the timing of the decision, but was associated with several accepted tumor factors. This study shows that, contrary to the opinion of some, there is a group of breast cancer patients in whom treatment in a one-step manner is appropriate.