Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE.

BACKGROUND: In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. PATIENTS AND METHODS: KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). RESULTS: The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR = 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. CONCLUSIONS: T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.

Safety and immunogenicity of neoadjuvant treatment using WT1-immunotherapeutic in combination with standard therapy in patients with WT1-positive Stage II/III breast cancer: a randomized Phase I study.

PURPOSE: This Phase I, multicenter, randomized study (ClinicalTrials.gov NCT01220128) evaluated the safety and immunogenicity of recombinant Wilms' tumor 1 (WT1) protein combined with the immunostimulant AS15 (WT1-immunotherapeutic) as neoadjuvant therapy administered concurrently with standard treatments in WT1-positive breast cancer patients. METHODS: Patients were treated in 4 cohorts according to neoadjuvant treatment (A: post-menopausal, hormone receptor [HR]-positive patients receiving aromatase inhibitors; B: patients receiving chemotherapy; C: HER2-overexpressing patients on trastuzumab-chemotherapy combination; D: HR-positive/HER2-negative patients on chemotherapy). Patients (cohorts A-C) were randomized (2:1) to receive 6 or 8 doses of WT1-immunotherapeutic or placebo together with standard neoadjuvant treatment in a double-blind manner; cohort D patients received WT1-immunotherapeutic in an open manner. Safety was assessed throughout the study. WT1-specific antibodies were assessed pre- and post-vaccination. RESULTS: Sixty-two patients were randomized; 60 received ≥ one dose of WT1-immunotherapeutic. Two severe toxicities were reported: diarrhea (cohort C; also reported as a grade 3 serious adverse event) and decreased left ventricular ejection fraction (cohort B; also reported as a grade 2 adverse event). Post-dose 4 of WT1-immunotherapeutic, 10/10 patients from cohort A, 0/8 patients from cohort B, 6/11 patients from cohort C, and 2/3 patients from cohort D were humoral responders. The sponsor elected to close the trial prematurely. CONCLUSIONS: Concurrent administration of WT1-immunotherapeutic and standard neoadjuvant therapy was well tolerated and induced WT1-specific antibodies in patients receiving neoadjuvant aromatase inhibitors. In patients on neoadjuvant chemotherapy or trastuzumab-chemotherapy combination, the humoral response was impaired or blunted, likely due to either co-administration of corticosteroids and/or the chemotherapies themselves.

Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)†.

BACKGROUND: The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline-taxane-based neoadjuvant chemotherapy increases pathological complete response (pCR) rates overall and specifically in patients with triple-negative breast cancer (TNBC). No difference in pCR rate was observed for adding everolimus to paclitaxel in nonearly responding patients. Here, we present disease-free (DFS) and overall survival (OS) analyses. PATIENTS AND METHODS: Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without eight infusions of bevacizumab every 3 weeks before surgery. Patients without clinical response to EC ± Bevacizumab were randomized to 12 weekly cycles paclitaxel with or without everolimus 5 mg/day. To detect a hazard ratio (HR) of 0.75 (α = 0.05, ß = 0.8) 379 events had to be observed in the bevacizumab arms. RESULTS: With a median follow-up of 3.8 years, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.784 for DFS and HR 0.974; P = 0.842 for OS) compared with patients receiving chemotherapy alone. Patients with TNBC similarly showed no improvement in DFS (HR = 0.99; P = 0.941) and OS (HR = 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1-3 or cT4; pCR or not) showed a significant benefit. No difference in DFS (HR 0.997; P = 0.987) and OS (HR 1.11; P = 0.658) was observed for nonearly responding patients receiving paclitaxel with or without everolimus overall as well as in subgroups. CONCLUSIONS: Long-term results, in opposite to the results of pCR, do not support the neoadjuvant use of bevacizumab in addition to an anthracycline-taxane-based chemotherapy or everolimus in addition to paclitaxel for nonearly responding patients. CLINICAL TRIAL NUMBER: NCT 00567554, www.clinicaltrials.gov.

Neoadjuvant bevacizumab and anthracycline-taxane-based chemotherapy in 678 triple-negative primary breast cancers; results from the geparquinto study (GBG 44).

BACKGROUND: We evaluated the pathological complete response (pCR) rate after neoadjuvant epirubicin, (E) cyclophosphamide (C) and docetaxel containing chemotherapy with and without the addition of bevacizumab in patients with triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Patients with untreated cT1c-4d TNBC represented a stratified subset of the 1948 participants of the HER2-negative part of the GeparQuinto trial. Patients were randomized to receive four cycles EC (90/600 mg/m(2); q3w) followed by four cycles docetaxel (100 mg/m(2); q3w) each with or without bevacizumab (15 mg/kg; q3w) added to chemotherapy. RESULTS: TNBC patients were randomized to chemotherapy without (n = 340) or with bevacizumab (n = 323). pCR (ypT0 ypN0, primary end point) rates were 27.9% without and 39.3% with bevacizumab (P = 0.003). According to other pCR definitions, the addition of bevacizumab increased the pCR rate from 30.9% to 41.8% (ypT0 ypN0/+; P = 0.004), 36.2% to 46.4% (ypT0/is ypN0/+; P = 0.009) and 32.9% to 43.3% (ypT0/is ypN0; P = 0.007). Bevacizumab treatment [OR 1.73, 95% confidence interval (CI) 1.23-2.42; P = 0.002], lower tumor stage (OR 2.38, 95% CI 1.24-4.54; P = 0.009) and grade 3 tumors (OR 1.68, 95% CI 1.14-2.48; P = 0.009) were confirmed as independent predictors of higher pCR in multivariate logistic regression analysis. CONCLUSIONS: The addition of bevacizumab to chemotherapy in TNBC significantly increases pCR rates.

Duration of dysmenorrhoea and extent of adenomyosis visualised by magnetic resonance imaging.

OBJECTIVE: Enlargement of the junctional zone (JZ) on T2-weighted resonance imaging of the uterus has recently been established as the major criterion for adenomyosis in patients with endometriosis. This study was conducted to analyse the extent of adenomyosis using magnetic resonance imaging (MRI) and relate it to the duration of dysmenorrhoea. STUDY DESIGN: This was a prospective study of 70 patients presenting with the complaint of severe dysmenorrhoea. Forty patients (57%) reported dysmenorrhoea as their major complaint and 30 patients (43%) suffered additionally from infertility. Group I (n=40) consisted of patients with dysmenorrhoea of between 1 and 10 years' duration, group II (n=30) consisted of patients with dysmenorrhoea of longer than 11 years' duration. All patients underwent laparoscopy to detect the presence and degree of endometriosis, and all patients underwent T2-weighted resonance imaging of the uterus to detect the extent of adenomyosis by measurement of the "junctional zone". RESULTS: In group I, adenomyosis could be detected via MRI in 21 patients (52.5%), while 19 patients (47.5%) showed no signs of adenomyosis. By contrast, in group II a distinct enlargement of the JZ, as the major radiological criterion of adenomyosis, could be observed in 26 patients (87%), while only 4 patients (13%) revealed no signs of adenomyosis (p=0.04). The mean thickness of the JZ was significantly enlarged in group II (11.07 mm) compared with group I (6.38 mm; p<0.0001). The prevalence of adenomyosis in endometriosis after dysmenorrhoea of more than 11 years' duration was 87%. CONCLUSIONS: In deep infiltrating endometriosis, a correlation between a specific localisation and dysmenorrhoea can often not be found. Recently, endometriosis and adenomyosis have been believed to result from a common uterine disease, the dislocation of the basal endometrium. Our data clearly show that dysmenorrhoea of long duration in patients who have had endometriosis for over a threshold value of 11 years is significantly related to adenomyosis of the uterus. Hence, evaluation of adenomyosis using MRI should become a standard procedure in cases of dysmenorrhoea and endometriosis. Severe dysmenorrhoea of long duration should always focus clinical interest on adenomyosis of the uterus.

[Preventing cardiovascular disease in type 2 diabetes. From evidence based medicine to patient based reality]. / Prévention de la maladie coronarienne chez le diabétique de type 2. Des preuves à la pratique.

The vascular complications of type 2 diabetes are the principal causes of morbidity and mortality. The prevention of vascular complications is the cornerstone of diabetes management. It includes early and regular screening of cardiovascular risk factors and multifactorial interventions promoting life-style and a step-wise introduction of medical treatment, most frequently multimedication. Overall, the management of these patients implies involving them as the main actors of their disease management. We need to take into account of their beliefs and their priorieties to seek actively the causes of non compliance and beyond evidence based medicine to accompany them in choosing the interventions they are ready to invest themself.

[Preventing type 2 diabetes complications: from evidence-based recommendations to patient-based reality]. / Prévenir les complications du diabète de type 2: des recommandations evidence-based a la réatité patient-based.

The vascular complications of type 2 diabetes count for the principal causes of morbidity, hospitalisation and mortality in this population. Therefore, preventing these complications is the cornerstone of the management of these patients. This prevention is through multifactorial interventions aiming at controlling the parameters of the metabolic syndrome in order to prevent or slow down these vascular complications. This prevention is also through a regular and exhaustive screening performed early enough in the disease. Above all, the management of these patients implies involving them as the main actors of their disease and treatments. This necessitates to take into account the beliefs and to actively seek the obstacles to therapeutic adherence.

Molecular genetics of antithrombin deficiency.

Antithrombin is the major proteinase inhibitor of thrombin and other blood coagulation proteinases. Antithrombin has two functional domains, a heparin binding site and a reactive centre (that complexes and inactivates the proteinase). Its deficiency results in an increased risk of venous thromboembolism. Appreciable progress has been made in recent years in understanding the structure and function of this protein, the genetic cause of inherited deficiency and its clinical consequence. The structure of antithrombin is now considered in terms of the models derived from X-ray crystallography, which have provided explanations for the function of its heparin interaction site and of its reactive loop. The structural organization of the antithrombin gene has been defined and numerous mutations have been identified that are responsible for antithrombin deficiency: these may reduce the level of the protein (Type I deficiency), alter the function of the protein (Type II deficiency, altering heparin binding or reactive sites), or even have multiple or 'pleiotropic effects' (Type II deficiency, altering both functional domains and the level of protein).

A mutation in the thrombomodulin gene, 127G to A coding for Ala25Thr, and the risk of myocardial infarction in men.

Thrombomodulin is an endothelial cell surface receptor that transforms the procoagulant thrombin into an anticoagulant. A mutation in the thrombomodulin gene is a potential risk factor for venous and arterial thrombosis. We screened a region within the coding sequence of the thrombomodulin gene by single-strand conformation polymorphism analysis (SSCP) in a pilot study of 104 patients with myocardial infarction and 104 age, sex and race matched controls. We identified a 127G to A mutation in the gene, which predicts an Ala25Thr substitution, in 2 out of 104 patients (1 man and 1 woman) with myocardial infarction but in no controls. We assessed the risk of myocardial infarction associated with the mutation in a larger "Study of Myocardial Infarctions Leiden" (SMILE). Among 560 men with a first myocardial infarction before the age of 70, 12 were carriers of the Ala25Thr substitution. In a control group of 646 men, frequency-matched for age, seven were carriers of the Ala25Thr substitution. The allelic frequencies were 1.07% among patients and 0.54% among controls suggesting risk associated with the mutation [odds ratio (OR) 2.0, 95% confidence interval (CI) 0.8-5.1]. In patients aged below 50, the predicted risk was almost seven times increased (OR 6.5, CI 0.8-54.2). In the presence of additional risk factors, such as smoking and a metabolic risk factor, the predicted risk increased to 9-fold (OR 8.8. CI 1.8-42.2) and 4-fold (OR 4.4, CI 0.9-21.3), respectively. While not conclusive, these results strongly suggest that the Ala25Thr substitution is a risk factor for myocardial infarction, especially in young men, and when in the presence of additional risk factors.

Regulation of amyloid precursor protein release by protein kinase C in Swiss 3T3 fibroblasts.

Release of the amyloid precursor protein (APP) of Alzheimer's disease from Swiss 3T3 fibroblasts was stimulated in a concentration-dependent manner by phorbol 12-myristate 13-acetate. In fibroblasts overexpressing protein kinase C alpha (PKC alpha), the EC50 for this response was 7 nM, while in control cells the EC50 was 63 nM. The effect of PMA was inhibited by the PKC antagonist H-7 in control cells, but not in cells that overexpressed PKC alpha. Basal release of APP was higher in cells that overexpressed PKC alpha, and was not affected by the phosphatase inhibitor okadaic acid, although this compound doubled APP release from control cells. The results suggest that PKC alpha regulates APP processing in mammalian cells. Alterations in the activity of PKC have been reported to occur in Alzheimer's disease and might potentially contribute to abnormalities of APP metabolism characteristic of this disorder.

Psychological distress, perceived health status, and physician utilization in America and West Germany.

This paper reports on findings pertaining to levels of psychological distress, perceived health status, and physician utilization among a sample of Americans (N = 1204) and West Germans (N = 1266) living in Illinois and North-Rhine Westphalia, respectively. The conflicting perspectives of labeling theory and the clinical approach to cross-cultural variations in mental disorder are discussed. There were no significant differences between the two population groups with respect to anxiety tendencies or psychological distress generally, with the exception of Germans having significantly more tendency toward depression. In both countries, persons with the lowest expressions of anxiety were the most likely to perceive symptoms of physical problems as requiring a doctor's attention, thereby suggesting that anxiety operates to influence a denial of general readiness to deal with symptoms. Yet persons with the highest anxiety, depression, and overall psychological distress were most likely to report having experienced physical symptoms and visiting a doctor because of it. Persons with the highest anxiety, depression, and overall psychological distress also rated their health status the lowest.

Health lifestyles and self-direction in employment among American men: a test of the spillover effect.

This paper examines whether American males with a high degree of control over their work situation pursue healthy lifestyles and rate their physical health more positively than those who score low on occupational self-direction. That is, are persons who control their work more likely to also try to control their health through living in a particularly healthy manner? We found that there was no support for a spillover effect from high occupational self-direction to enhanced participation in health lifestyles or more positive self-rated health. The findings suggest health lifestyles have spread throughout occupational work groups in the U.S. and support research that maintains such lifestyles have spread across social strata in America.

Symptoms, social stratification and self-responsibility for health in the United States and West Germany.

This study compares the responses of a sample of Americans in Illinois and West Germans in North-Rhine Westphalia on the basis of symptom perception, symptom experience, physician utilization and health-locus-of-control. The hypothesis that as socioeconomic status increases, the more likely the individual is to manifest and behavior favorable toward self-control and acceptance of personal responsibility in health care matters was tested. The hypothesis was supported by the American data, but not the West German. Possible trends in West German society accounting for a significant lack of socioeconomic variance in illness behavior are discussed.

After unification: gender and subjective health status in East and West Germany.

Results of a random survey of 2574 adults in East and West Germany in 1992 show virtually no differences in subjective health status for the populations of East versus West Germany and only slight differences for men versus women. A closer analysis via multiple regression indicates, however, that contrary to previous results from other countries West German women have a better health status than men. Of the four gender groups analyzed separately East German men are the best off, while owing to a number of socio-economic status discrepancies, East German women report the worst health status. Surprisingly, West German men show a poorer subjective health status than East German men, although a number of factors like participation in sport, better income and younger age would predict otherwise. It is suggested that their health situation is negatively influenced not only by their work situation but also by outside private commitments not accounted for in this analysis. Also difficult to explain from the present data is the relatively good health status of East German men. Despite an insecure job and a difficult work situation they may experience unification in sociopolitical terms and their present social status as something positive. Overall, conditions in the system of West Germany show a tendency to favor women, while those in East Germany clearly favor men.

[Examination of the image quality from digital fluoroscopy equipment with 1k- and 2k-image matrix]. / Untersuchungen zur Bildqualität von Durchleuchtungsanlagen mit 1k- und 2k-Bildmatrix.

PURPOSE: The image quality of 1k- and 2k-radiographs from digital fluoroscopy equipments (Sireskop SX and Polystar SX--Siemens) are characterized by comparison with each other to evaluate the relevance of this technique in clinical routine. MATERIAL AND METHODS: We examined fabricated and evaluated images with 1k- and 2k-image matrix from several high and low contrast phantoms and from skeleton phantoms. On the one hand, the digital image values can be used directly for the evaluation, on the other hand the comparing evaluation by experienced radiologists resulted from a visual consideration in a blind study. RESULTS: The quality difference of the 1k- and 2k-images depends mainly on the distance of the investigated sector of the object to the image intensifier and on the scattering of the radiation in the object positioned between the investigated sector and the image intensifier. The nearer the investigated object is located to the intensifier and the smaller the radiation is scattered in the object, the more the image quality of a radiograph with a 2k-matrix is increasing in comparison to an image with 1k-matrix. The higher the tube voltage, the smaller are the differences. CONCLUSION: The image quality enhancement because of the more sensitive sampling of the Saticon target in the 2k-matrix is limited by the opening of the iris positioned in the light distributor. Therefore the image quality differences of medical 1k- and 2k-radiographs in many cases are small.

The uterine peristaltic pump. Normal and impeded sperm transport within the female genital tract.

Rapid as well as sustained sperm transport from the cervical canal to the isthmical part of the fallopian tube is provided by cervico-fundal uterine peristaltic contractions that can be visualized by vaginal sonography. The peristaltic contractions increase in frequency and presumably also in intensity as the proliferative phase progresses. As shown by placement of labeled albumin macrospheres of sperm size at the external cervical os and serial hysterosalpingoscintigraphy (HSSG) sperm reach, following their vaginal deposition, the uterine cavity within minutes. In the early follicular phase a large proportion of the macrospheres remains at the site of application, while a smaller proportion enters the uterine cavity with even a smaller one reaching the isthmical part of the tubes. In the mid-follicular phase of the cycle with increased frequency and intensity of the uterine contractions the proportion of macrospheres entering the uterine cavity as well as the tubes has significantly increased. In the late follicular phase with maximum frequency and intensity of uterine peristalsis the proportion of macrospheres entering the tube increases further at the expense of those at the site of application as well as within the uterine cavity. The transport of the macrospheres into the tube is preferentially directed into the tube ipsilateral to the dominant follicle, which becomes apparent in the mid-follicular phase as soon as a dominant follicle can be identified by ultrasound. Since the macrosphere are inert particles the directed sperm transport into the tube ipsilateral to the dominant follicle is not functionally related to a mechanism such as chemotaxis but is rather provided by uterine contraction of which the direction may be controlled by a specific myometrial architecture in combination with an asymmetric distribution of myometrial oestradiol receptors. Women with infertility and mostly mild endometriosis display on VSUP a uterine hyperperistalsis with nearly double the frequency of contractions during the early and mid- as well as midluteal phase in comparison to the fertile and healthy controls. During midcycle these women display a considerable uterine dysperistalsis in that the normally long and regular cervico-fundal contractions during this phase of the cycle have become more or less undirected and convulsive in character. Hyperperistalsis results in the transport of inert particles from the cervix into the tubes within minutes already during the early follicular phase, and may therefore constitute the mechanical cause for the development of endometriosis in that it transports detached endometrial cells and tissue fragments via the tubes into the peritoneal cavity. Moreover, dysperistalsis may contribute to the infertility in these patients since it results in a break down of sperm transport within the female genital tract.

[Influence of tandem optics and television tube of modern digital fluoroscopy equipment on image quality]. / Einfluss von Tandemoptik und Fernsehaufnahmeröhre moderner Durchleuchtungsanlagen auf die Bildqualität.

The influence of the tandem optics and the TV-tube to the image quality of 1k- and 2k-radiographs of a modern fluoroscopy equipment should be assessed on the basis of objective parameters and clinical requirements. Radiographs of different phantoms with 1k- and 2k-image matrix, different illumination point corrections (IPC) and signal gray levels were taken, examined and evaluated, in order to determine the objective image parameters and the clinical relevancy of these parameters. On the one hand, the digital images data could be used directly for evaluation; on the other hand, the radiographs could be visually evaluated by experienced radiologists within the framework of a blind study. The IPC is controlled by the aperture of the iris diaphragm and the insertion of a neutral gray filter in the tandem optics. The larger the aperture of the iris diaphragm (at constant image receiver dose) the higher were gradation, signal to noise ratio (SNR) and image homogeneity. Furthermore, the larger the aperture, the lower was the square wave response function (SWRF). The insertion of a gray filter in the tandem optics decreases gradation, SNR and homogeneity, and improves the SWRF.

Evaluating strategies to improve careprovider performance on health and developmental tasks in an infant care facility.

Responding to administrative staff and parental concerns, using modified reversal and withdrawal designs, two experiments evaluated a staff-managed feedback system to improve the hygiene and developmental skills of children in an infant/toddler center. Experiment 1 examined feedback designed to increase staff performance in checking and changing diapers, and recording those changes. A chart plus supervisory feedback produced increases in and maintenance of staff performance. Experiment 2 compared an existing staff management system with a "playchart" plus feedback in increasing careprovider-infant stimulation. The data (with follow-up on a new staff) supported the use of the new feedback system. Questionnaire data further supported the utility of the playchart system.

Pre-eruptive intracoronal lesion of a mandibular first molar.

A patient developed an acute apical abscess on a mandibular first molar with an intact occlusal sealant. Radiographs reveal no typical patterns of decay on occlusal or proximal surfaces. An unusual lesion within dentin and an apparent extension from it to the external tooth surface are visible on films at the time of onset of symptoms as well as prior to eruption. Possible explanations for the lesion and its progression are discussed.