Percentiles of intrauterine placental volume and placental volume relative to fetal volume: A prospective magnetic resonance imaging study.

INTRODUCTION: We aimed to provide percentiles of intrauterine placental growth and placental growth relative to fetal growth (placental to fetal ratio) by measuring placental and fetal volumes by magnetic resonance imaging (MRI). METHODS: In this prospective study, 107 unselected singleton pregnancies were examined by MRI at gestational week 27 and 37. Based on the estimated volumes of the placenta and the fetus, we calculated median and percentiles at gestational weeks 27 and 37. RESULTS: Median placental volume at gestational week 27 was 513 cm3 (Inter Quartile Range (IQR) 182 cm3), and 831 cm3 (IQR 252 cm3) at week 37. The 10th - 90th percentiles included placental volumes between 392 and 717 cm3 at gestational week 27, and 631-1087 cm3 at week 37. The placental to fetal ratio was significantly higher at gestational week 27 than at week 37, with a median ratio of 0.54 (IQR 0.18) and 0.31 (IQR 0.08), respectively (p < 0.001). The 10th-90th percentiles included placental to fetal ratios between 0.43 and 0.73 at gestational week 27 and 0.25-0.39 at week 37. DISCUSSION: At gestational week 27, the placental volume was about half the size of the fetal volume, whereas at week 37, the placental volume was about one third of the fetal volume. This finding suggests that placental growth was less prominent than fetal growth after gestational week 27. Knowledge about the distribution of intrauterine placental size in the general population of pregnancies are prerequisites for diagnosing abnormal placental size.

Quality-of-life scores predict outcome in metastatic but not early breast cancer. International Breast Cancer Study Group.

PURPOSE: We compared the prognostic value of quality-of-life (QL) scores in the adjuvant setting and after relapse in two randomized trials of the International Breast Cancer Study Group. PATIENTS AND METHODS: More than 2,000 premenopausal and postmenopausal patients with node-positive breast cancer who were participating in randomized trials that compared adjuvant therapies completed QL assessments for physical well-being, mood, appetite, and coping at study entry and at months 3 and 18 if they remained relapse-free and, in case of relapse, at 1 month and at 6 months after relapse. Cox regression models were used to test the relationship between QL scores and disease-free survival (DFS), in the adjuvant setting, or overall survival, in the case of postrelapse QL measurement. All models were stratified by language/country group and included other factors related to QL and/or outcome. RESULTS: DFS was not significantly predicted by QL scores at baseline or month 18, or by changes in QL score between baseline and months 3 or 18. In contrast, after relapse, QL scores were predictive for subsequent overall survival. One month after relapse, better mood (P =.04) in premenopausal patients and better appetite (P =.005) in postmenopausal patients were associated with longer survival. Six months after relapse, better physical well-being (P =.03) and appetite (P =.03) in premenopausal patients and better physical well-being (P <.0001), mood (P =.002), appetite (P =.0001), and coping (P =.0001) in postmenopausal patients predicted longer survival. CONCLUSION: Any prognostic significance of QL scores in the adjuvant setting is minimal or obscured by chemotherapy effects, but there is strong prognostic significance of QL scores after disease relapse. The contrast suggests that patient perception of the severity of underlying illness may determine reported QL scores.

Role of immunohistochemical detection of lymph-node metastases in management of breast cancer. International Breast Cancer Study Group.

BACKGROUND: This study was designed to ascertain whether immunohistochemical methods could improve the detection of metastases in primary breast-cancer patients whose axillary lymph nodes were classified, by conventional methods, as disease free. METHODS: Ipsilateral lymph nodes (negative for metastases by routine histology) from 736 patients (participants in Trial V of the International [Ludwig] Breast Cancer Study) were examined by serial sectioning and staining with haematoxylin and eosin (two sections from each of six levels) and by immunohistochemistry of a single section (with two anticytokeratins AE-1 and CAM 5.2). After median follow-up of 12 years, disease-free and overall survival were estimated by Kaplan-Meier methods. FINDINGS: Occult nodal metastases were detected by serial sectioning and haematoxylin and eosin in 52 (7%) of 736 patients and by immunohistochemistry in 148 (20%). Only two (3%) of 64 invasive lobular or mixed invasive lobular and ductal cancers had node micrometastases, detected by haematoxylin and eosin, compared with 25 (39%) by immunohistochemistry. Occult metastases, detected by either method, were associated with significantly poor disease-free and overall survival in postmenopausal but not in premenopausal patients. Immunohistochemically detected occult lymph-node metastases remained an independent and highly significant predictor of recurrence even after control for tumour grade, tumour size, oestrogen-receptor status, vascular invasion, and treatment assignment (hazard ratio 1.79 [95% CI 1.17-2.74], p=0.007). INTERPRETATION: The immunohistochemical examination of ipsilateral axillary lymph nodes is a reliable, prognostically valuable, and simple method for the detection of occult nodal metastases. Immunohistochemistry is recommended as a standard method of node examination in postmenopausal patients.

Factors affecting baseline quality of life in two international adjuvant breast cancer trials. International Breast Cancer Study Group (IBCSG).

Quality of life (QL) is used to assess treatments in clinical trials but may be influenced by other factors. We analysed the impact of biomedical, sociodemographic and cultural factors on baseline QL indicators in two International Breast Cancer Study Group trials. Patients with stage II breast cancer were randomized within 6 weeks of primary surgery to various adjuvant treatments. They were asked to assess five indicators of QL at baseline. QL forms were available for 1231 (83%) of the 1475 premenopausal and 989 (82%) of the 1212 post-menopausal patients, who were from nine countries and spoke seven languages. Culture (defined as language/country groups) had a statistically significant impact on baseline QL measures. Premenopausal patients with poor prognostic factors showed a tendency to report worse QL, with oestrogen receptor status as an independent predictor for mood (P = 0.0005). Older post-menopausal patients reported better emotional wellbeing (P = 0.002), mood (P = 0.002), and less effort to cope (P = 0.0009) compared with younger post-menopausal patients. Co-morbidity, type of surgery, treatment assignment and sociodemographic factors showed a statistically significant impact in post-menopausal patients only. Cultural and biomedical factors influenced baseline QL and should be considered when evaluating the impact of treatment on QL in international breast cancer clinical trials.

Quality of life assessment in International Breast Cancer Study Group (IBCSG) trials: practical issues and factors associated with missing data.

We report on our experience of quality of life (QL) assessment in adjuvant clinical trials of the International Breast Cancer Study Group (IBCSG), with special emphasis on cultural and logistical aspects of international organization that are unique to this group. Data are presented regarding submission rates of assessments before and after treatment failure, and timing of assessments relative to chemotherapy administration. To identify areas where rates might be improved, we investigated the association between missing data and sociodemographic and biomedical factors, treatment assignment, institution, chemotherapy compliance and toxicity in a trial of adjuvant chemoendocrine therapy for post-menopausal patients with breast cancer (IBCSG VII). The factors most highly associated with missing data were institution and chemotherapy compliance.

Why are missing quality of life data a problem in clinical trials of cancer therapy?

Assessment of health related quality of life has become an important endpoint in many cancer clinical trials. Because the participants of these trials often experience disease and treatment related morbidity and mortality, non-random missing assessments are inevitable. Examples are presented from several such trials that illustrate the impact of missing data on the analysis of QOL in these trials. The sensitivity of different analyses depends on the proportion of assessments that are missing and the strength of the association of the underlying reasons for missing data with disease and treatment related morbidity and mortality. In the setting of clinical trials of cancer therapy, the assumption that the data are missing completely at random (MCAR) and analyses of complete cases is usually unjustified. Further, the assumption of missing at random (MAR) may also be violated in many trials and models appropriate for non-ignorable missing data should be explored. Recommendations are presented to minimize missing data, to obtain useful documentation concerning the reasons for missing data and to perform sensitivity analyses.

Comparison of several model-based methods for analysing incomplete quality of life data in cancer clinical trials.

This paper considers five methods of analysis of longitudinal assessment of health related quality of life (QOL) in two clinical trials of cancer therapy. The primary difference in the two trials is the proportion of participants who experience disease progression or death during the period of QOL assessments. The sensitivity of estimation of parameters and hypothesis tests to the potential bias as a consequence of the assumptions of missing completely at random (MCAR), missing at random (MAR) and non-ignorable mechanisms are examined. The methods include complete case analysis (MCAR), mixed-effects models (MAR), a joint mixed-effects and survival model and a pattern-mixture model. Complete case analysis overestimated QOL in both trials. In the adjuvant breast cancer trial, with 15 per cent disease progression, estimates were consistent across the remaining four methods. In the advanced non-small-cell lung cancer trial, with 35 per cent mortality, estimates were sensitive to the missing data assumptions and methods of analysis.

Quality of life assessment in patients receiving adjuvant therapy for breast cancer: the IBCSG approach. The International Breast Cancer Study Group.

BACKGROUND AND PURPOSE: The International Breast Cancer Study Group (IBCSG) has developed and approach for assessing the impact of adjuvant therapy on quality of life (QL) within the framework of international, multilingual clinical trials. The major steps are summarized. Conceptual, methodological and practical issues are discussed with reference to results of two trials closed to accrual (IBCSG VI, VII) and one subsequent ongoing trial (IBCSG IX). PATIENTS AND METHODS: QL was assessed in pre- and post-menopausal patients with operable breast cancer. Various single-item linear analogue self-assessment (LASA) scales were used as indicators of components of QL, including global indicators of well-being, functioning and health perception, and specific indicators of symptoms of disease and treatment. In trials VI and VII, QL was assessed at baseline, during adjuvant treatment and follow-up, and at recurrence. Based on this experience, the QL form was revised for subsequent trials and further investigated in a subsample of patients randomized into trial IX. RESULTS: In trials VI and VII, the QL indicators were responsive to the impact of biomedical factors at baseline, various adjuvant treatments, changes over the first 18 months, and recurrence. In trial IX, the revised QL form was well accepted by patients and staff. Completing this form did not exceed five minutes. QL differences between on and off cytotoxic treatment strengthen the claim that these measures are responsive. Correlations and logistic regression analyses show the expected relationship among the various global and specific indicators. CONCLUSION: Results from two trials closed to accrual and an ongoing trial confirm the feasibility, validity and clinical relevance of the IBCSG approach for studying the impact of adjuvant breast cancer therapy on QL in international clinical trials.

Prognostic importance of thymidylate synthase expression in early breast cancer.

PURPOSE: To assess the prognostic importance of thymidylate synthase (TS) expression in breast tumors of patients with early-stage breast cancer, and to determine whether the benefit of chemotherapy (CT) is associated with TS expression. PATIENTS AND METHODS: The level of TS expression was evaluated in 210 node-negative and 278 node-positive patients enrolled onto Trial V of the International Breast Cancer Study Group ([IBCSG] formerly the Ludwig Breast Cancer Study Group) with a median follow-up time of 8.5 years. TS expression was assessed using the immunohistochemical method with the monoclonal antibody TS 106 on paraffin-embedded tissue specimens. RESULTS: High TS expression was associated with a significantly worse prognosis in node-positive but not in node-negative breast cancer patients. Twenty-seven percent of node-positive patients with high TS expression were disease-free at 10 years, compared with 44% of node-positive patients with low TS expression (P = .03). Forty-one percent of patients with node-positive high-TS-expressing tumors were alive after 10 years, compared with 49% of those with low TS expression (P = .06). The association between TS and disease-free survival (DFS) and overall survival (OS) was independent of other prognostic factors such as tumor size, tumor grade, nodal status, vessel invasion, estrogen receptor (ER)/ progestin receptor (PR) status, c-erb B-2, or Ki-67 expression. In node-positive patients, six cycles of standard adjuvant cyclophosphamide, methotrexate, and fluorouracil ([5-FU] CMF) CT improved DFS and OS compared with one cycle of perioperative CMF therapy. The magnitude of this benefit was greatest in patients whose tumors had high TS expression (P < .01 for DFS; P < .01 for OS). Node-negative patients demonstrated no difference in outcome to CT based on TS expression; however, the power to detect differences was limited by the small number of events in this group. CONCLUSION: In early-stage breast cancer, high TS expression is associated with a significantly worse prognosis in node-positive patients. Node-positive patients with high TS levels demonstrate the most significant improvement in DFS and OS when treated with six cycles of conventional adjuvant CMF therapy.

What makes quality assurance effective? Results from a randomized, controlled trial in 16 primary care group practices.

OBJECTIVES: The authors estimate separately contributions of each component intervention to overall effectiveness of quality assurance cycles used to improve practice performance. METHODS: In a randomized, controlled trial, experimental cycles of quality assurance were conducted for eight patient-care guidelines, with two experimental cycles assigned to each of 16 group practices. For three separate interventions per cycle, practitioners: (1) were notified of the name of the experimental guideline, (2) discussed criteria of conformance to the guideline, and (3) received feedback on performance. Actions taken in response to interventions were documented. Using medical records data for a baseline year and for 3 months after each intervention and an additional 9 months, the authors scored each practice for conformance to two experimental guidelines and to control guidelines. RESULTS: For all patient-care guidelines combined, and for four of five guidelines showing improvement, knowledge of guidelines and review criteria alone produced no change. After feedback, performance improved and improvement persisted for at least 9 months. The number of corrective actions implemented contributed significantly to effectiveness of quality assurance. CONCLUSIONS: Feedback to providers of data on their performance is a more powerful stimulus for quality improvement than is knowledge of guidelines or discussion of review criteria.

Impact of adjuvant therapy on quality of life in women with node-positive operable breast cancer. International Breast Cancer Study Group.

BACKGROUND: Adjuvant therapy for early breast cancer is effective but may be toxic. Our aim was to investigate the impact of the presence, timing, and duration of adjuvant chemotherapy on patients' perceptions of their quality of life (QL). METHODS: International Breast Cancer Study Group trial VI assessed adjuvant chemotherapy in 1475 premenopausal and perimenopausal patients, and trial VII assessed adjuvant tamoxifen or chemoendocrine therapy in 1212 postmenopausal patients with node-positive breast cancer. Patients were asked to complete a QL questionnaire-single-item linear analogue self-assessment scales measured physical wellbeing, mood, appetite, and perceived adjustment/coping. QL was assessed in this way at the beginning of treatment, 2 months after the start of treatment, every 3 months, and at 1 and 6 months after recurrence. FINDINGS: Baseline QL scores decreased as the number of involved axillary nodes increased (for example, mean mood score: 66.1 for women with one positive node, 66.4 for two to four positive nodes, 61.3 for five to nine positive nodes, and 59.1 for ten or more positive nodes; p = 0.008 for trends), and were lower in patients with oestrogen-receptor-negative than in patients with oestrogen-receptor-positive tumours (61.4 vs 66.3, p = 0.0009). All treatment groups showed substantial improvement in QL scores during adjuvant therapy. Patterns of QL scores reflected presence, duration, and timing of cytotoxic treatment. Longer initial cytotoxic therapy delayed improvement in QL scores. Later cytotoxic therapy had transient adverse effects. Anticipation of future therapy also affected QL scores. INTERPRETATION: Overall, chemotherapy had a measurable adverse effect on QL, but this effect was transient and minor compared with patients' adaptation/coping after diagnosis and surgery. This finding should encourage patients and doctors to choose appropriate adjuvant therapy with less concern for initial toxicity.

Responsiveness of a single-item indicator versus a multi-item scale: assessment of emotional well-being in an international adjuvant breast cancer trial.

A single-item linear analogue self-assessment scale for mood was compared with a 28-item adjective checklist for emotional well-being. To confirm its concurrent validity and responsiveness to treatment and recurrence in patients with breast cancer, emotional well-being was assessed every 3 months for 2 years and at 1 and 6 months after recurrence in 1,169 patients who were premenopausal and 960 patients who were postmenopausal. These patients were enrolled in two International Breast Cancer Study Group randomized clinical trials in operable breast cancer conducted from 1986 to 1993. To assess concurrent validity, Pearson's correlation between the linear analogue self-assessment scale and the adjective checklist were calculated for each time-point within each treatment group and for the two assessments after recurrence. Responsiveness to treatment and recurrence were analyzed using paired t tests and the squared ratio of these t tests, an estimate of relative efficiency. Concurrent validity of the mood linear analogue self-assessment was consistently confirmed across four language groups. Both measures were responsive; out of 24 changes over time, 19 were in the expected direction for the linear analogue self-assessment scale (p < or = 0.05 for 9 of 19) and 17 for the adjective checklist (p < or = 0.05 for 10 of 17). The linear analogue self-assessment scale was less but significantly efficient for detection of treatment effects, with relative efficiency estimates ranging from 0.16 to 2.45 and a median of 0.66 among the comparisons with relatively stable estimates (/t/ > or = 1.0) and more efficient for recurrence than the adjective checklist. The mood linear analogue self-assessment scale is a valid indicator of emotional well-being in patients with breast cancer in large multicenter, multicultural trials in which comprehensive scales are less feasible. This investigation supports the clinical relevance of linear analogue self-assessment scales as indicators of components of quality of life in cancer clinical trials.

Central venous catheter sepsis with weekly catheter change in paediatric burn patients: an analysis of 221 catheters.

To document the risk of catheter sepsis associated with central venous catheter changes every 7 days in paediatric burn patients, and analysis of data collected prospectively on 234 such catheters was performed. During an 18-month period there were 301 acutely burned children admitted to a regional paediatric burn facility of whom 53, with an average burn size of 42 per cent TBSA, required 234 central venous catheters. A central venous catheter management protocol was followed which included catheter changes every 7 days. If insertion sites were clean and uninflamed, catheters were replaced by guidewire and the original catheter tip was semiquantitatively cultured. Catheters were replaced to a new site if insertion sites appeared inflamed or catheter tips grew 15 or more colony forming units. Overall, 3.2 per cent (10.9 per cent by Centers for Disease Control definition) of central venous catheters were associated with sepsis. When catheters were replaced by guidewire from one to three times, catheter sites were used for a mean of 15.6 days without an increased rate of line sepsis. There was no difference in sepsis rates between catheters placed at a new site or replaced by guidewire. There were no deaths attributed to catheter-related sepsis. We conclude that a protocol allowing for catheter change to a new site, or replacement by guidewire, every 7 days was associated with a low risk of catheter sepsis in paediatric burn patients.

Timing of baseline quality of life assessment in an international adjuvant breast cancer trial: its effect on patient self-estimation. The International Breast Cancer Study Group.

BACKGROUND: Variability in timing of baseline quality of life (QL) assessments in two ongoing International Breast Cancer Study Group (IBCSG) randomized clinical trials occurred as a result of allowing some flexibility in the timing. This retrospective report describes the QL timing in relation to surgery and start of adjuvant therapy and its effect on QL self-estimation. PATIENTS AND METHODS: Self-administered measures of baseline QL were obtained on day 1 of adjuvant therapy or as close to that date as possible from 1389 pre- and post-menopausal women with operable breast cancer. RESULTS: Fifty-four percent of QL assessments were done on day 1 of adjuvant therapy, 18% before day 1 and 28% after. An ANOVA, controlling for surgery, institution and language, showed that: for patients receiving endocrine therapy alone, QL improved as time from surgery increased, but start of adjuvant treatment had no effect, while for chemotherapy patients, appetite, physical well-being and, in pre-menopausal patients, coping were worse 1 to 5 days after the start of treatment. Chemotherapy had little effect on mood and emotional well-being. CONCLUSIONS: Timing of QL assessment in relation to diagnosis affects global adjustment measures; timing in relation to chemotherapy affects measures sensitive to toxicity. Timing is an important consideration in study conduct and data analysis.

Factors predicting treatment responsiveness and prognosis in node-negative breast cancer. The International (Ludwig) Breast Cancer Study Group.

PURPOSE: An international trial (formerly Ludwig Trial V) has been conducted in 1,275 subjects to ascertain if perioperative chemotherapy is beneficial for node-negative breast cancer patients and to identify subgroups of patients who benefit from this therapy. PATIENTS AND METHODS: Node-negative breast cancer patients were randomized to receive either one cycle of perioperative chemotherapy or no adjuvant treatment. A detailed pathology review was conducted in 1,203 of the 1,275 patients enrolled. Stepwise Cox regression analysis was used to search for factors either predicting chemotherapeutic responsiveness and/or influencing disease-free survival (DFS). RESULTS: As expected, primary tumor size, grade, and the presence of peritumoral vascular invasion are the most important prognostic factors. Perioperative chemotherapy provides a DFS advantage at 5 years of median follow-up and such treatment is more effective for estrogen receptor-negative than for estrogen receptor-positive tumors, for histologic grade 2 and 3 than for grade 1 tumors, and for patients in whom no axillary lymph node metastases were found even after serial sectioning and review by the Central Pathology Laboratory. CONCLUSION: Hormone receptor status and tumor grade are important factors for predicting responsiveness to perioperative chemotherapy in node-negative breast cancer.

Effects of various hippocampal lesions on monkey plasma cortisol levels in two experimental conditions.

The plasma cortisol levels of Rhesus monkeys with anterior, posterior, or near-total hippocampal lesions were compared to controls during two separate stressful conditions. In the first condition, each monkey was placed for the first time in a primate restraint chair for 72 h. In the second condition each monkey performed a complex behavioral task (titrating shock avoidance) to control the intensity of frequent footshock for a 24-h period. Control subjects had either no surgical operation or else surgical exposure of the hippocampus with no hippocampal lesion. They manifested lower plasma cortisol levels during shock avoidance compared with during the chair condition. Subjects with posterior hippocampal lesions manifested the same pattern but near-totally hippocampectomized subjects showed an opposite pattern with cortisol levels higher in the shock avoidance condition compared with the chair condition. Subjects with anterior hippocampal lesions had similar cortisol levels in both conditions. Thus hippocampal modulation of corticosteroid levels may depend on the specific condition under which such levels are measured, and may be relatively more subserved by anterior compared with posterior hippocampus in the monkey.

A randomized controlled trial of quality assurance in sixteen ambulatory care practices.

A crossover randomized controlled trial of cycles of quality assurance in 16 primary care (8 medical, 8 pediatric) group practices was conducted. Of four medical and four pediatric tasks important to patient outcome, two were randomly assigned to experimental intervention (a quality assurance cycle), and two were also measured and used as blinded controls for each medical or pediatric group practice. Task performance was measured in each group for 12 months prior to, 9 months during, and 9 months after the experimental intervention, using as a performance score the percentage of evaluation criteria failed of those applicable to a case. As a result of quality assurance intervention, quality of performance was significantly improved in two of the tasks (P less than 0.0001, with 6.7, and 9.8 percentage points improvement), and marginally improved in one task (P = 0.06, 5.7 percentage points improvement). Surprisingly, tasks with lower perceived effect on patient health (low physician motivation) had greater improvement in quality. Unimproved tasks were associated with the perceived need for delivery system changes beyond the immediate control of the individual practitioner.

Surgical and radiological decompression in malignant biliary obstruction: a retrospective study using multivariate risk factor analysis.

We performed a retrospective computer-aided statistical study of 228 patients who received treatment for malignant biliary obstruction to compare survival rates after surgical or radiological biliary decompression. To adjust for the selection bias produced by the clinical choice of surgical vs. catheter drainage, we examined differences in survival rates after controlling for various clinical and laboratory factors, which are predictive of short and long-term survival. These factors were selected by multivariate analysis. Short-term survival was significantly correlated with preoperative metabolic status as reflected in serum albumin, and blood urea nitrogen (BUN) levels. Elevated serum bilirubin values had no additional negative effect on survival. Long-term survival was influenced mainly by the extent of the primary cancer and the preoperative presence of leukocytosis. Although there was a difference in the raw data for hospital mortality between patients who underwent surgical drainage (11%) and those who underwent radiological drainage (30%), we found no real effect produced by the form of therapy after controlling for prognosis variables, i.e., eliminating selection bias. We propose a simple statistical model to predict short-term hospital survival. The application of objective risk factor analysis according to accepted statistical methods should permit the assessment of new radiologic therapeutic techniques with greater clinical validity.