Impact of patients' refusal to undergo adjuvant treatment measures on survival.

PURPOSE: Breast cancer patients receive treatment recommendations from multidisciplinary tumour boards. To determine the consequences of patients' refusal of such recommendations, we analysed the database of the Centre for Breast Cancer at the Ortenau Clinic in Offenburg, Germany. METHODS: A total of 4315 patients with non-metastatic primary breast cancer, treated between 1997 and 2019, were analysed with descriptive analyses, Kaplan-Meier survival analyses, and Cox regression analyses regarding the effects of their refusal. RESULTS: About 10.7% of the patients rejected the treatment advice. These were significantly elderly (F = 74.4; p < 0.001; one-way ANOVA), with greater tumour size (F = 36.7; p < 0.001; one-way ANOVA), a higher number of affected lymph nodes (F = 4.2; p = .039; one-way ANOVA), and more poorly differentiated tumours (χ2 = 16.8; df = 2; p < 0.001). The refusal of adjuvant treatment resulted in higher rates of local recurrences (χ2radiotherapy = 109.1; df = 1; p < 0.001, χ2chemotherapy = 18.3; df = 1; p < 0.001, χ2endocrine = 32.5; df = 1; p < 0.001) and poorer overall survival (χ2radiotherapy = 184.9; df = 6; p < 0.001; χ2chemotherapy = 191.8; df = 6; p < 0.001). CONCLUSIONS: All parts of the adjuvant treatment of breast cancer are clearly associated with improvements regarding disease-free and overall survival. To answer open questions about the background of patients' refusal, an analysis of prospective data collections seems necessary. In addition, patient communication should be improved so that patients understand the background of the multidisciplinary tumour board and the potential consequences of their refusal.

Influence of side-effects on early therapy persistence with letrozole in post-menopausal patients with early breast cancer: Results of the prospective EvAluate-TM study.

BACKGROUND: Endocrine treatment (ET) with an aromatase inhibitor (AI) is the treatment of choice in post-menopausal patients with hormone receptor-positive early breast cancer (EBC). However, adverse events (AEs) often lead to treatment discontinuation. This analysis aimed to identify side-effects that lead to patients failing to persist with letrozole treatment. PATIENTS AND METHODS: Post-menopausal hormone receptor-positive EBC patients starting ET with letrozole were enroled in EvAluate-TM, a non-interventional study. Information regarding treatment compliance and persistence was gathered in months 6 and 12. Persistence was defined as the time from 30 d after the start to the end of treatment. The influence on persistence of musculoskeletal syndrome, menopausal disorder, sleep disorder and other AEs within the first 30 d was analysed using Cox regression analyses. RESULTS: Among 3887 patients analysed, the persistence rate after 12 months was >85%. In all, 568 patients (14.6%) discontinued the treatment, 358 of whom (63.0%) did so only because of side-effects. The main AEs influencing persistence were musculoskeletal symptoms (hazard ratio [HR] 2.55; 95% confidence interval [CI], 1.90-3.42), sleep disorders (HR 1.95; 95% CI, 1.41-2.70) and other AEs (HR 2.03; 95% CI, 1.51-2.73). Menopausal disorder was not associated with non-persistence (HR 1.17; 95% CI, 0.74-1.84). CONCLUSIONS: These results suggest that side-effects of AIs such as musculoskeletal syndrome and sleep disorder lead to ET discontinuation within the first treatment year in significant numbers of EBC patients. Compliance programmes adapted for subgroups that are at risk for early non-persistence might help to ensure the recommended therapy duration. CLINICAL TRIALS NUMBER: CFEM345DDE19.

Influence of patient and tumor characteristics on early therapy persistence with letrozole in postmenopausal women with early breast cancer: results of the prospective Evaluate-TM study with 3941 patients.

Background: Patients' compliance and persistence with endocrine treatment has a significant effect on the prognosis in early breast cancer (EBC). The purpose of this analysis was to identify possible reasons for non-persistence, defined as premature cessation of therapy, on the basis of patient and tumor characteristics in individuals receiving adjuvant treatment with letrozole. Patients and methods: The EvAluate-TM study is a prospective, multicenter, noninterventional study in which treatment with the aromatase inhibitor letrozole was evaluated in postmenopausal women with hormone receptor-positive EBC in the early therapy phase. Treatment persistence was evaluated at two pre-specified study visits after 6 and 12 months. As a measure of early therapy persistence the time from the start to the end of treatment (TTEOT) was analyzed. Cox regression analyses were carried out to identify patient characteristics and tumor characteristics predicting TTEOT. Results: Out of the total population of 3941 patients with EBC, 540 (13.7%) events involving treatment cessation unrelated to disease progression were observed. This was due to drug-related toxicity in the majority of cases (73.5%). Persistence rates were 92.2%, 86.9%, and 86.3% after 6, 12, and 15 months, respectively. The main factors influencing premature treatment discontinuation were older age [hazard ratio (HR) 1.02/year], comorbidities (HR 1.06 per comorbidity), low body mass index, and lower tumor grade (HR 0.85 per grade unit). Conclusion: These results support the view that older, multimorbid patients with low tumor grade and low body mass index are at the greatest risk for treatment discontinuation and might benefit from compliance and support programs.

Evaluation of Therapy Management and Patient Compliance in Postmenopausal Patients with Hormone Receptor-positive Breast Cancer Receiving Letrozole Treatment: The EvaluateTM Study.

Introduction: The EvaluateTM study (Evaluation of therapy management and patient compliance in postmenopausal hormone receptor-positive breast cancer patients receiving letrozole treatment) is a prospective, non-interventional study for the assessment of therapy management and compliance in the routine care of postmenopausal women with invasive hormone receptor-positive breast cancer receiving letrozole. The parameters for inclusion in the study are presented and discussed here. Material and Methods: Between January 2008 and December 2009 a total of 5045 patients in 310 study centers were recruited to the EvaluateTM study. Inclusion criteria were hormone receptor-positive breast cancer and adjuvant treatment or metastasis. 373 patients were excluded from the analysis for various reasons. Results: A total of 4420 patients receiving adjuvant treatment and 252 patients with metastasis receiving palliative treatment were included in the study. For 4181 patients receiving adjuvant treatment, treatment with the aromatase inhibitor letrozole commenced immediately after surgery (upfront). Two hundred patients had initially received tamoxifen and started aromatase inhibitor treatment with letrozole at 1-5 years after diagnosis (switch), und 39 patients only commenced letrozole treatment 5-10 years after diagnosis (extended endocrine therapy). Patient and tumor characteristics were within expected ranges, as were comorbidities and concurrent medication. Conclusion: The data from the EvaluateTM study will offer a good overview of therapy management in the routine care of postmenopausal women with hormone receptor-positive breast cancer. Planned analyses will look at therapy compliance and patient satisfaction with how information is conveyed and the contents of the conveyed information.

[Fetomaternal transfusions in complicated and uncomplicated pregnancy]. / Fetomaternale Transfusionen bei kompliziertem und unkompliziertem Schwangerschaftsverlauf.

Fetomaternal bleeding in pregnancy is the most common cause of rhesus immunization. In this study we evaluated the amount of fetomaternal bleeding during pregnancies with and without complications. The data from 1204 patients are analyzed. Fetomaternal bleeding was of clinical relevance (HbF greater than 0.01%) in 6% of all uncomplicated pregnancies. There was no increased fetomaternal bleeding in pregnancies complicated by gestosis, preliminary labour, placenta praevia, trauma, and diabetes in pregnancy. In cases with premature rupture of the amnion or vaginal bleeding in pregnancy we observed an increased percentage of fetomaternal bleeding into the mother's circulation. Nearly 25% of all patients with hydrops fetalis had clinical relevant fetomaternal bleeding (HbF greater than 0.01%).

[Fetomaternal transfusions in early pregnancy]. / Fetomaternale Transfusionen in der Frühschwangerschaft.

Fetomaternal bleeding is the major cause for rhesus immunization in pregnancy. This study evaluates the amount of fetomaternal bleeding in 345 pregnancies before 28th week of gestation. Fetomaternal bleeding was of clinical relevance (HbF greater than 0.015%) in 2.2% of all uncomplicated pregnancies. In case of abortion or vaginal bleeding in early pregnancy we observed a statistical significant increase of transplacental hemorrhage. The need for anti-D-prophylaxis in this patients is obvious.

Vascular tumor in the heart.

A rare case of a vascular tumor originating from the uterus growing up in the inferior vena cava into the right heart with clinical signs of tricuspid insufficiency is reported. Although this vascular tumor primarily showed no signs of malignancy, consequent re-evaluation seems to be necessary in order to detect possible tumor recurrence in time.

[Prognosis of pregnancy in diabetes mellitus]. / Zur Prognose der Schwangerschaft bei Diabetes mellitus.

From 1970-1984 116 pregnant diabetic patients were monitored and delivered at the University Hospital of Freiburg, Department of Obstetrics and Gynecology. During these 15 years, a decrease in maternal and fetal complications was observed. Today the risk of some complications in diabetic pregnancy is not greater than that of pregnancy in nondiabetic women. There is, however, still a higher incidence of gestosis and polyhydramnion in diabetics. The main fetal risk is macrosomia. There is an increasing tendency to spontaneous delivery near term. Today incidence rate of caesarean sections is below 30%.

[Monitoring of pregnancy in diabetes mellitus]. / Die Uberwachung der Schwangerschaft bei Diabetes mellitus.

From 1970-1984 116 diabetic pregnant patients were monitored and delivered at the University Hospital of Freiburg, Department of Obstetrics and Gynaecology. The pregnant diabetics were managed and controlled by an interdisciplinary team of internists and obstetricians. For better control of the maternal metabolic status, the diabetic patients were admitted to the hospital three times during their pregnancy. Foetal monitoring was done by ultrasonography, hormone analyses and cardiotocography. In most cases foetal growth retardation and macrosomia were detected early via sonography. Decreased urinary excretion of total oestrogen was measured during late pregnancy in 13% of the diabetic patients. In cardiotocography a loss of foetal reactivity was observed in 11% of all non-stress tests (NST). In more than 50% of these cases, the total oestrogen excretion also decreased. In patients with normal oestrogen values, an abnormal NST was rarely observed. Abnormal oxytocin challenge tests (OCT) were recorded in 19% of the patients. Among these cases most of the patients with a non-reactive NST were found. In 85% of the patients with pathological changes in the OCT a Caesarean section had to be performed, and among these in all patients with a loss of foetal reactivity in the cardiotocogram. In correlation with the foetal outcome, loss of reactivity in the cardiotocogram has greater pathological relevance than deceleration with maintenance of reactivity. For an early recognition of imminent placental insufficiency, OCT proved to be the most sensitive parameter. The increased incidence of acute placental insufficiency in diabetics during delivery underlines the need for repeated stress tests during late pregnancy.

Characterization of growth factors in human ovarian carcinomas.

Epidermal growth factor (EGF)-like factors with EGF competing and cell growth stimulating activity were investigated in malignant and nonmalignant tissues. About 37% of ovarian carcinomas present an increased factor activity between 9.0 and 19.3 ng EGF units/mg protein. In one tumor 175.0 ng EGF units/mg protein were found. In extracts of nonmalignant tissues, the factor concentration was about 1.0-6.4 ng EGF units/mg protein. Isoelectric focusing was performed to characterize these factors. In normal ovaries and ovarian carcinomas, factors with EGF competing activity focus at pH 8.0-9.0, pH 5.7-6.3, and pH 3.6-4.9. In ovarian carcinomas, an additional peak with EGF competing and cell growth stimulating activity was found between pH 6.5 and 7.2. Similar results could be achieved in other malignant tissues investigated. These data indicate the presence of EGF-like factors. EGF itself focuses at pH 4.6 (G. Carpenter and S. Cohen, Annu. Rev. Biochem., 48: 193-216, 1979). Specific EGF binding was determined in 12 ovarian carcinomas. In five of these cases EGF receptors could be detected. In the EGF receptor positive carcinomas, the content of EGF-like growth factors varied between 0 and 9 ng EGF units/mg protein. In EGF receptor negative cases, the content of EGF-like growth factors varied between 0 and 19.3 ng EGF units/mg protein. The clinical data of 19 patients are also demonstrated.

Rapid sexing of native amniotic cells by hybridization to a cloned Y chromosome DNA probe.

A cloned DNA fragment from a Y chromosome genomic library was used for prenatal sex determination. Native cells from as little as 0.5 ml of amniotic fluid were analyzed by a dot blot hybridization technique without prior cell culture. Identification of male fetuses was possible within 3 days and confirmed by subsequent conventional karyotyping. This method of rapid sex screening is an alternative to the other methods of prenatal determination to the conventional chromosome analysis because it is a more rapid method, and to the karyotyping of chorion biopsy material because amniocentesis seems to have a lower risk and can still be performed when chorion biopsy is not more possible.

The influence of gonadotropic hormones on the EGF receptor regulation in the rat ovary.

Ovaries of immature rats are endowed with only a small number of EGF binding sites (59.2 X 10(-15) mol/mg protein). During development from day 20 to 28, the binding capacity increases 2.5 times, while the growth of the ovaries remains small. Treatment with FSH on day 20 advances the EGF binding capacity with a 4-fold increase in the number of binding sites within the first two days. HCG has no or only a slight effect on the EGF binding capacity. The EGF receptor formation after FSH treatment takes place before the ovaries begin to grow rapidly. Accelerated ovarian growth is associated with a decrease of EGF binding capacity reaching values below those of the control animals during the subsequent days. The dissociation constants (KD) of the FSH stimulated receptors and of receptors present during development are found in the order of 2.7 and 8.7 X 10(-9) M. The physiological function of the EGF receptor for ovarian cell proliferation and follicular growth is discussed.

[Rh-incompatibility acidosis in newborn infants following intrauterine transfusion]. / Rh-Inkompatibilität-Azidose bei Neugeborenen nach intrauteriner Transfusion.

Severe foetal Rh erythroblastosis is treated by intrauterine transfusion, in most cases with ACD adenine erythrocyte concentrates. In two cases where delivery took place shortly after the last intrauterine transfusion, metabolic acidosis developed post partum, which could possibly be attributed to the erythrocyte concentrates in the transfusion. Multiple pH level measurements in the ACD adenine erythrocyte concentrates revealed pH levels between 6.4 and 6.8. Erythrocyte concentrates prepared with heparin showed pH levels between 7.18 and 7.25 and should therefore be used for intrauterine transfusion in place of ACD adenine erythrocyte concentrates.

[Value of antepartal cardiotocogram in risk pregnancies--comparative evaluation of the non-stress test and oxytocin stress test]. / Wertigkeit des antepartalen Kardiotokogramms bei Risikoschwangerschaften--Vergleichende Beurteilung des Non-Stress-Testes und des Oxytocin-Belastungstestes.

247 patients with risk of uteroplacental insufficiency were monitored by 434 oxytocin challenge tests (OCT) and non-stress-tests (NST). A non-reactive NST was found in 20% of the patients. Late decelerations in the OCT were observed in 19%. With respect to late decelerations and loss of reactivity in the OCT, the results of the stress tests were pathological in 29% of the patients. Based on the evaluation of late decelerations only, the OCT does not appear to be superior to the NST. Only when the reactivity criterion is additionally taken into account can the diagnostic rating of the OCT be given more value than that of the NST. Furthermore, it could be established that the loss of reactivity is of greater importance than late decelerations in the presence of reactivity.

[Rhesus erythroblastosis, monitoring and treatment]. / Rhesuserythroblastose, Uberwachung und Behandlung.

From 1975-1984 92 pregnancies with suspicion of a morbus hemolyticus fetalis were monitored at the University Hospital of Freiburg, Department of Obstetrics and Gynecology. Most of the patients had antibodies against the rhesusfactor D. Amniocentesis was carried out regularly; the bilirubin level and protein content of the amniotic fluid were measured using chemical methods and the bilirubin/protein ratio was determined. The results obtained correlated well with the values of spectrophotometrically measured bilirubin, which reliably indicated the severity of the hemolytic disease. A serious erythroblastosis was observed in 17 cases. Four children died before any treatment was initiated. In 13 children 37 intrauterine transfusions (IUT) were performed. The survival rate of the children with IUT's was 69%, in nonhydropic children it was 82%. The mortality risk of the IUT was low. Children with IUT's often showed complications in the perinatal period, which were due to the premature birth and the erythroblastosis.

Crosslinking of HCG to its specific receptor of porcine ovarian membranes.

HCG receptors of porcine ovarian plasma membranes were loaded with 125I-hCG and covalently crosslinked with glutaraldehyde. The plasma membranes were labeled with tritium. The hCG receptor complex was solubilized in 1% SDS and subsequently chromatographed on Biogel P 300. 40-50% of 125I-radioactivity eluted near the void volume. 3H radioactivity in these fractions indicated the presence of crosslinked hormone receptor complexes. A second minor peak of 125I-radioactivity appeared at 55000 d. A third peak represented subunits of 125I-hCG. Analysis of the Biogel P 300 purified 125I-hCG receptor complex by polyacrylamide gel electrophoresis in sodium dodecyl sulfate resulted in two radioactivity peaks. The main peak corresponded to 90 000-100 000 d, the second peak was calculated to approximately 140 000 d. As a result the majority of the hormone receptor complex has a molecular weight of 90 000-100 000 d. Existence of subunits is discussed.

The effect of prostaglandins in the rat ovary: specific or unspecific stimulation of cAMP, cGMP and progesterone?

Ovarian membranes of the rat do not specifically bind prostaglandin E2 at any stage of development. Attachment of [3H]prostaglandin E2 in the presence of an excess of unlabelled prostaglandin E2 increased in a linear fashion and was not saturable. Prostaglandin E2 stimulated cAMP accumulation by ovarian cells of all developmental stages. This effect was not saturable. An effect of prostaglandin E2 on cGMP levels was not observed. At high concentrations of prostaglandin E2 an increase of ovarian progesterone synthesis was detected. In comparison hCG stimulated progesterone synthesis at much lower concentrations. PGF2 alpha increased cellular and extracellular cAMP at 1000-fold higher concentrations than PGE2 and did not affect cGMP levels.

Development and regulation of the prostaglandin F2 alpha receptor in the rat ovary.

Ovaries of adult rats specifically bind PGF2 alpha while those of immature animals do not. Induction of luteinization by hCG in juvenile animals, however, results in specific binding of PGF2 alpha. It is suggested that luteal cells are the only cell type of the ovary, which is endowed with specific receptors for PGF2 alpha. The number of PGF2 alpha binding sites varies during the ovarian cycle. Most free receptors are detectable in early pro-oestrus, least in the oestrus stage. The oscillation of receptors disappears after inhibition of prostaglandin synthesis by indomethacin. Therefore the apparent cyclic variation of prostaglandin receptors must be ascribed to occupancy of the receptors by varying amounts of endogenous prostaglandin F2 alpha.

In vitro inactivation of gonadotropin receptors, a membrane-associated action?

Under in vitro conditions the time-dependent inactivation process of LH/HCG receptors is nearly identical in ovarian and testicular homogenates but different in gonadal membrane preparations. In the ovarian membranes the loss of binding sites during the first preincubation time is faster than in testicular membranes, especially in membranes of luteinized rat ovaries. Compared with the homogenates, however, the receptor-inactivation in the membranes is generally delayed. The inhibitory effect of metabolic agents on receptor inactivation indicates that membrane-associated actions are involved in this process.