Retrospective analysis of the prognostic significance of DNA content and proliferative activity in large bowel carcinoma.

In the present study we have evaluated the prognostic significance of ploidy levels and proliferative activity in 279 cases of large bowel carcinomas which were included in a surgical prospective randomized trial. Ploidy levels and proliferative activity were determined on nuclei isolated from paraffin-embedded tissues of 279 colorectal carcinoma patients, with a mean follow-up of 51.9 months. Product limit survival analysis demonstrated a borderline significant association (P = 0.0689 by generalized Breslow; P = 0.0336 by generalized Savage) between ploidy and survival, with a 75th quantile survival of 49.8 months for patients with diploid tumors and 35.9 months for patients with aneuploid tumors. After stratification for staging, Dukes' C cases showed a statistically significant association between tumor ploidy and survival (P = 0.0224 by generalized Breslow, P = 0.0110 by generalized Savage). Product limit survival analysis for proliferative activity and survival showed a similar outcome with the strongest association in Dukes's C stage of disease (75th quantile survival of 38.9 months for low proliferative and 18.0 months for high proliferative tumors).

Loco-regional recurrences after mastectomy in breast cancer: prognostic factors and implications for postoperative irradiation.

PURPOSE: Potential risk factors including DNA flow cytometric-derived parameters predicting loco-regional recurrence (LRR) in early breast cancer were investigated. MATERIALS AND METHODS: This study included 608 patients treated by modified radical mastectomy between 1982 and 1987. Recommendations regarding local treatment as well as adjuvant systemic therapy did not change during this period. Patients treated by adjuvant chemotherapy were randomized to receive additional medroxyprogesterone acetate (MPA) treatment. Only 59 (10%) patients received postoperative irradiation (XRT) to the chest wall and/or axillary lymph nodes; another 121 (20%) patients received XRT to the internal mammary nodes because of centromedially located tumours. RESULTS: Patients were followed for a median period of 7.5 years. The event-free survival at 10 years was 50%. The cumulative incidence rate of LRR at 10 years was 18% (n = 93), either with (n = 30) or without (n = 63) concurrent distant metastases. The chest wall, regional lymph nodes or both were involved in 41 (44%), 38 (41%) and 12 (13%) patients, respectively. Multivariate analysis according to the Cox model revealed two factors associated with LRR, i.e. pT (P < 0.05) and nodal status (P < 0.05). In node-positive patients extracapsular tumour extension (ECE) and pT were independent risk factors. DNA ploidy and S-phase fraction did not yield additional information. Based on pT, nodal status and extracapsular extension of tumour growth a high risk (> 10%) and low risk (< 10%) group for LRR could be identified. CONCLUSIONS: Results indicate that T-stage and nodal status, combined with ECE, may help to identify patients at risk for loco-regional recurrence, whereas DNA flow cytometry does not.

Relation between endometrial wavelike activity and fecundability in spontaneous cycles.

OBJECTIVE: To determine whether endometrial activity is related to the occurrence of pregnancy in spontaneous menstrual cycles. DESIGN: Prospective observational ultrasound evaluation of endometrial activity during fertility screening cycles. SETTING: University hospital-based infertility clinic. PATIENT(S): Fifty-nine fertility screening cycles (ultrasound monitoring of follicle growth and ovulation, postcoital test, semen analysis, midluteal P, Chlamydia antibody determination, and tubal patency testing) were performed in 47 couples complaining of infertility. In 33 couples (37 cycles), no fertility impairing factors were found. Endometrial activity was analyzed in these cycles. INTERVENTION(S): Ultrasound examination was performed transvaginally throughout the cycle. MAIN OUTCOME MEASURE(S): Endometrial activity, wave pattern, pregnancy. RESULTS(S): Nine women conceived within the cycle studied. Conception cycles showed less-activity compared with nonconception cycles. Endometrial wavelike activity increased throughout the follicular phase and decreased after ovulation in conception and nonconception cycles. CONCLUSION(S): Endometrial activity is related to fecundability in a spontaneous cycle.

Adjuvant chemo-hormonal therapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) with or without medroxyprogesterone acetate (MPA) for node-positive cancer patients, update at 12 years follow up.

An update with 10 years of follow up of a study adding adjuvant MPA to CAF chemotherapy is presented. A total of 409 patients were entered, of which 200 were randomized to receive 500 mg of MPA i.m. on days 1-28 and twice per week thereafter for 6 months. There was a significant improvement in metastases-free and overall survival in women >60 years of age receiving MPA (P=0.01 and P=0.02 respectively). A detrimental effect of MPA was seen in women <40 years. Possible reasons for these results are discussed.

Anti-apoptotic phenotype is associated with decreased locoregional recurrence rate in breast cancer.

PURPOSE: Tumor stage and nodal status are the most important factors predicting locoregional recurrence in breast cancer. We wanted to investigate the prognostic value of some newer molecular genetic markers for the occurrence of a locoregional recurrence, in order to improve the selection of patients for locoregional adjuvant therapy. METHODS: Bcl-2, p53, MIB-1, pS2 and CD44v6 were determined immunohistochemically on formalin-fixed and paraffin embedded tumour tissues of 163 patients treated by modified radical mastectomy between 1982 and 1987. Postoperative irradiation was given to 35 patients to the intermammary chain only and to only 13 (8%) patients to the chest wall with or without the regional lymph nodes. Node-positive patients were treated with CAF adjuvant chemotherapy and were randomized for whether or no additional Medroxyprogesteroneacetate (MPA). A multivariate analysis was performed on a number of potential prognostic factors. The risk for locoregional recurrence was estimated using the competing risk approach. RESULTS: After a median period of 7.5 years 28 patients developed a locoregional recurrence. The cumulative incidence of loco-regional recurrence at 10 years was 17%. Bcl-2 and p53 were found to be independent factors predicting locoregional recurrence, whereas a trend was found for MIB-1. Increased Bcl-2 as well as p53 expression were associated with a decreased risk, whereas the increased presence of MIB-1 was associated with an increased risk. CONCLUSION: Results indicate that molecular markers of apoptosis as well as proliferation provide additional information for the risk of locoregional recurrence after modified radical mastectomy. If confirmed, these markers may play a role in the selection of appropriate locoregional adjuvant treatment after primary surgery.

The prognostic significance of steroid receptor activity in tumor tissues of patients with primary breast cancer.

The prognostic significance of steroid-receptor activity is still debatable. Discrepancies in results are probably attributable to few patients, heterogeneous patient populations, and short follow-up. We investigated the prognostic significance of estrogen- and progesterone-receptor (ER and PgR, respectively) activity as a continuous variable in a homogeneous patient population. The prognostic significance of steroid-receptor activity was examined in 329 node-negative and 320 node-positive unselected breast cancer patients. In node-negative patients, ER values of primary tumors between 100 and 400 fmol/mg protein appeared to be a significant predictor for low risk of recurrence, whereas high ER (> 400) revealed an unfavorable prognosis. The classic cutoff level of ER (< 10 fmol/mg proteins) had no prognostic significance, however. In patients receiving adjuvant chemotherapy--the node-positive breast cancer patients--the classic cutoff value of ER (10 fmol/mg protein) predicts significantly distant metastases-free survival and overall survival only in the first 4 years of follow-up after diagnosis. Progesterone receptor is a time-dependent prognosticator in node-negative breast cancer patients (cutoff point for PgR, 80 fmol/mg). In node-positive breast cancer patients treated with chemotherapy or a combination of chemo- and hormonal therapy, PgR values lower than 60 fmol/mg had a worse prognosis. The results show the poor performance of standard cutoff points for ER and PgR positivity in predicting prognosis. Better prognosis is related to higher receptor levels but this relation is predominantly time-dependent. Moreover, patients who have high ER levels have a prognosis that is worse when compared with intermediate ER levels. Standard cutoff points for steroid receptors should not be used to select patients for prognosis.

Mammography in the follow-up after breast-conserving treatment in cancer of the breast: suitability for mammographic interpretation, validity and interobserver variation.

The aims of this study were to determine the suitability for radiographic interpretation, interobserver variability and validity of mammography after breast-conserving treatment. Initial and post-treatment mammograms of 100 consecutive patients treated between 1982 and 1987, with a minimal follow-up of 5 years, were independently selected for review by two radiologists. Mammograms were classified according to suitability for interpretation and radiological diagnosis based on the presence of characteristics of malignancy. The interobserver variability was expressed in kappa values, the validity in a receiver operating characteristic (ROC) plot. 534 post-treatment and 86 initial mammograms of 92 patients were obtained. Suitability for interpretation was not different from pre-treatment mammograms and was significantly associated with age, being better in the age group over 50 years. No association was observed between suitability for interpretation and treatment-related factors, even if irradiation was combined with concurrent chemotherapy. Reliability of conclusions regarding sensitivity and specificity in this study are limited due to the small number of events. Interobserver agreement concerning classification was moderate (weighted kappa = 0.49). ROC analysis showed an optimal decision threshold between the "uncertain" and "suspect" categories of malignancy, resulting in a sensitivity of 86% and a specificity of 98%. The appearance of new pathological microcalcifications with or without tumour mass seemed to be the most important characteristics of malignancy predicting local relapse. No clear alteration in suitability for interpretation was observed in the mammograms after breast-conserving treatment, even if irradiation was combined with concurrent chemotherapy. Mammography after breast conserving-treatment may be slightly less sensitive but is equally specific compared with mammography in the screening situation.

[Functional treatment of Colles fractures and the relation of anatomic recovery and function]. / Functionele behandeling van Colles-fracturen en het verband tussen anatomisch herstel en functie.

Functional treatment of Colles fractures is a recently developed approach to fracture injury. It aims to bring about faster recovery and a better functional end result by permitting early motion and function by means of a functional brace. Early motion and function, however, might jeopardize the anatomical result. Whether an inferior anatomical result jeopardizes the functional end result is not clear, as the relationship between anatomy and function has not been established. In a prospective clinical study it was concluded that in displaced Colles fractures functional treatment with a below-the-elbow functional brace offers little advantage over conventional plaster of Paris immobilisation. Minimally displaced Colles fractures (volar angle greater than or equal to 0 degrees) should be treated with a bandage after one week of plaster immobilisation. The relationship between the anatomical and functional end result is weak and probably depends on initial displacement and complications. To improve the functional result after a Colles fracture, prevention and better treatment of complications seem to be more important than improvement of the method of fracture treatment of the anatomical end result.

A multivariate analysis of pathologic prognostic indicators in large bowel cancer.

A multivariate analysis of the pathologic data of 350 patients with primary colorectal cancer was performed. In addition to conventional parameters such as shape and size of the primary tumor, central node involvement, angioinvasive growth, grade, and stage, new variables such as the immunoreactivity patterns of carcinoembryonic antigen (CEA), CA 19-9, mucin, serotonin, secretory component (SC), and the DNA index were tested for their potential prognostic value. Every variable except CA 19-9, serotonin, and DNA showed significant prognostic information in univariate analysis. However, in the multivariate analysis stage was the predictive factor with the highest hazard ratio, but absence of central node involvement, tumors with diameters between 3.5 cm and 6 cm, exophytic tumor growth, well-differentiated tumors, tumors with CEA immunoreactivity, absence for staining with serotonin, and diploid tumors also were included in the relative risk model. Thus, the aforementioned variables appear to play a role in the establishment of a prognostic index.

Weight loss is a reversible factor in the prognosis of chronic obstructive pulmonary disease.

The objective of the study was to further unravel the prognostic significance of body weight changes in patients with COPD. Two survival analyses were performed: (1) a retrospective study, including 400 patients with COPD none of whom had received nutritional therapy; (2) a post hoc analysis of a prospective study, including 203 patients with COPD who had participated in a randomized placebo-controlled trial. There was no overlap between the patient groups. Baseline characteristics of all patients were collected on admission to a pulmonary rehabilitation center in stable clinical condition. In the prospective randomized placebo-controlled trial, the physiologic effects of nutritional therapy alone (n = 71) or in combination with anabolic steroid treatment (n = 67) after 8 wk was studied in patients with COPD prestratified into a depleted group and a nondepleted group. Mortality was assessed as overall mortality. The Cox proportional hazards model was used to quantify the relationship between the baseline variables age, sex, spirometry, arterial blood gases, body mass index (BMI), smoking, and subsequent overall mortality. Additionally, the influence of treatment response on mortality was investigated in the prospective study. The retrospective study revealed that low BMI (p < 0.001), age (p < 0.0001) and low PaO2 (p < 0.05) were significant independent predictors of increased mortality. After stratification of the group into BMI quintiles a threshold value of 25 kg/m2 was identified below which the mortality risk was clearly increased. In the prospective study, weight gain (> 2 kg/8 wk) in depleted and nondepleted patients with COPD, as well as increase in maximal inspiratory mouth pressure during the 8-wk treatment, were significant predictors of survival. On Cox regression analysis weight change entered as a time-dependent covariate remained an independent predictor of mortality in addition to all variables that were entered in the retrospective study. The combined results of the two survival analyses provide evidence to support the hypothesis that body weight has an independent effect on survival in COPD. Moreover the negative effect of low body weight can be reversed by appropriate therapy in some of the patients with COPD.

Prognostic significance of etiological risk factors in early breast cancer.

Several risk factors for the etiology of breast cancer have also been correlated with the prognosis of breast cancer. However, the published studies have yielded conflicting results. Women under 71 years of age with stage I, II, or III breast cancer were eligible for inclusion in a clinical study. 866 patients with breast cancer entered the study, of whom 463 had positive lymph nodes. Survival was analysed using Cox's proportional hazards model. Age at menarche parity, age at menopause and family history were not consistently related to survival. Young age at first full-term pregnancy was related to decreased survival (adjusted relative risk (RR): 1.69, 95% confidence intervals (95% CI): 1.04-2.68), but it cannot be excluded that this result was due to chance alone. Use of oral contraceptives was not correlated with survival (RR: 1.10, 95% CI: 0.80-1.51) nor was family history (RR: 0.93, 95% CI: 0.66-1.30). This study provided little support for the hypothesis that risk factors for breast cancer are related to survival.

Adjuvant chemohormonal therapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) with or without medroxyprogesterone acetate for node-positive breast cancer patients.

BACKGROUND: The Comprehensive Cancer Center trial 82-01 is a prospective randomized study to investigate the value of the addition of high-dose medroxyprogesterone acetate (MPA) to chemotherapy in patients with node-positive operable breast cancer. MPA may be of advantage in this setting because of its activity in estrogen receptor ER-positive as well as ER-negative tumors and since it may protect against chemotherapy-induced myelosuppression and thus enable maintenance of the appropriate chemotherapeutic scheduling. PATIENTS AND METHODS: Four hundred eight evaluable patients with node-positive (N+) operable breast cancer (T1-3, N1) were entered in a multicenter randomized trial. Two hundred nine patients were randomized in the MPA- arm and 199 in the MPA+ arm. CAF chemotherapy was given as a short i.v. bolus infusion: cyclophosphamide 500 mg/m2 i.v. day 1, doxorubicin 40 mg/m2 i.v. day 1, and 5-fluorouracil 500 mg/m2 i.v. day 1, q 4 wks x 6. MPA was given intramuscularly (i.m.) 500 mg q d x 28 days, followed by 500 mg i.m. twice weekly during 5 months. RESULTS: The main side effects of MPA were weight gain with a mean of 5.5 kg as opposed to 1.8 kg in the control group (p = 0.01) and vaginal bleeding in 30/199 in the MPA+ group and 0 in the MPA- group. MPA ameliorated vomiting grade III, IV (45% vs. 28%, p < 0.001), nausea grade III, IV (50% vs. 34%, p < 0.001) and leucocyte nadir grade III, IV (20% vs. 11%, p = 0.003). Disease-free survival (DFS) after 5 years was 59% in the MPA+ and 49% in the MPA- group (p = 0.12). Patients > or = 60 years benefitted most from MPA treatment, in particular if freedom from distant metastases was taken as the endpoint (p = 0.02). Overall survival (OS) was not significantly different between the two treatment groups (p = 0.18), but within subgroups analysed there was an advantage for MPA+ in patients > or = 55 years (p = 0.002) and in pT1 patients (p = 0.045). CONCLUSIONS: High-dose MPA ameliorates CAF side effects and reduces the risk of metastatic disease, especially in elderly breast cancer patients.

Psychosocial and physical correlates of survival and recurrence in patients with head and neck carcinoma: results of a 6-year longitudinal study.

BACKGROUND: Studies that have examined correlations between psychosocial factors and survival in cancer patients do not permit any definitive conclusions. To the authors' knowledge, to date no study has examined the relation between medical as well as quality of life variables and survival in head and neck carcinoma patients. The current study focused on the complex interactions among psychosocial, medical, behavioral, and demographic variables as they relate to prognosis in these patients. METHODS: A total of 133 consecutive head and neck carcinoma patients were included in a prospective study at pretreatment. In addition to clinical variables, psychosocial and physical functioning was assessed by means of a self-report questionnaire. RESULTS: During the observation period 57 patients died whereas 76 were still alive at 6 years after treatment. Results of the multivariate survival analysis indicated that patients without head and neck metastasis had a better prognosis than patients with positive cervical lymph nodes. Pretreatment smoking showed a negative correlation with overall survival. Patients who were more physically self-efficacious (i.e., higher perceived physical abilities) were more likely to survive and less likely to develop a recurrence. In addition, patients who expressed intense psychosocial complaints prior to treatment had a better prognosis than had those who did not express such negative feelings. CONCLUSIONS: The current findings linking physical self-efficacy and prognosis are promising, but clinical trials are necessary to examine the direct and indirect mediational pathways of the variables that underlie physical efficacy and influence survival and recurrence. Also, the negative correlation between pretreatment smoking and survival suggests a need for increased efforts to address smoking in newly diagnosed patients.