Martina Mittlböck

Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy

BACKGROUND The Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) bone substudy assesses zoledronic acid for preventing bone loss associated with adjuvant endocrine therapy and reports on long-term findings of bone-mineral density (BMD) during 3 years of treatment and 2 years after completing adjuvant treatment with or without zoledronic acid. The aim of this substudy is to gain insight into bone health in this setting. METHODS ABCSG-12 is a randomised, open-label, phase III, 4-arm trial comparing tamoxifen (20 mg/day orally) and goserelin (3.6 mg subcutaneously every 28 days) versus anastrozole (1 mg/day orally) and goserelin (3.6 mg subcutaneously every 28 days), both with or without zoledronic acid (4 mg intravenously every 6 months) for 3 years in premenopausal women with endocrine-responsive breast cancer. This prospective bone subprotocol measured BMD at 0, 6, 12, 36, and 60 months. The primary endpoint of the bone substudy (secondary endpoint in the main trial) was change in BMD at 12 months, assessed by dual-energy X-ray absorptiometry in assessable patients. Analyses were intention to treat. Statistical significance was assessed by t tests. The ABCSG-12 trial is registered on the ClinicalTrials.gov website, number NCT00295646. FINDINGS 404 patients were prospectively included in the bone substudy and randomly assigned to endocrine therapy alone (goserelin and anastrozole or goserelin and tamoxifen; n=199) or endocrine therapy concurrent with zoledronic acid (goserelin, anastrozole, and zoledronic acid or goserelin, tamoxifen, and zoledronic acid; n=205). After 3 years of treatment, endocrine therapy alone caused significant loss of BMD at the lumbar spine (-11.3%, mean difference -0.119 g/cm(2) [95% CI -0.146 to -0.091], p<0.0001) and trochanter (-7.3%, mean difference -0.053 g/cm(2) [-0.076 to -0.030], p<0.0001). In patients who did not receive zoledronic acid, anastrozole caused greater BMD loss than tamoxifen at 36 months at the lumbar spine (-13.6%, mean difference -0.141 g/cm(2) [-0.179 to -0.102] vs -9.0%, mean difference -0.095 g/cm(2) [-0.134 to -0.057], p<0.0001 for both). 2 years after the completion of treatment (median follow-up 60 months [range 15.5-96.6]), patients not receiving zoledronic acid still had decreased BMD at both sites compared with baseline (lumbar spine -6.3%, mean difference -0.067 g/cm(2) [-0.106 to -0.027], p=0.001; trochanter -4.1%, mean difference -0.03 g/cm(2) [-0.062 to 0.001], p=0.058). Patients who received zoledronic acid had stable BMD at 36 months (lumbar spine +0.4%, mean difference 0.004 g/cm(2) [-0.024 to 0.032]; trochanter +0.8%, mean difference 0.006 g/cm(2) [-0.018 to 0.028]) and increased BMD at 60 months at both sites (lumbar spine +4.0%, mean difference 0.039 g/cm(2) [0.005-0.075], p=0.02; trochanter +3.9%, mean difference 0.028 g/cm(2) [0.003-0.058], p=0.07) compared with baseline. INTERPRETATION Goserelin plus tamoxifen or anastrozole for 3 years without concomitant zoledronic acid caused significant bone loss. Although there was partial recovery 2 years after completing treatment, patients receiving endocrine therapy alone did not recover their baseline BMD levels. Concomitant zoledronic acid prevented bone loss during therapy and improved BMD at 5 years.

Explained variation for logistic regression.

Different measures of the proportion of variation in a dependent variable explained by covariates are reported by different standard programs for logistic regression. We review twelve measures that have been suggested or might be useful to measure explained variation in logistic regression models. The definitions and properties of these measures are discussed and their performance is compared in an empirical study. Two of the measures (squared Pearson correlation between the binary outcome and the predictor, and the proportional reduction of squared Pearson residuals by the use of covariates) give almost identical results, agree very well with the multiple R2 of the general linear model, have an intuitively clear interpretation and perform satisfactorily in our study. For all measures the explained variation for the given sample and also the one expected in future samples can be obtained easily. For small samples an adjustment analogous to Radj2 in the general linear model is suggested. We discuss some aspects of application and recommend the routine use of a suitable measure of explained variation for logistic models.

Efficacy of liver transplantation for alcoholic cirrhosis with respect to recidivism and compliance.

Many transplant centers are reluctant to accept alcoholic patients for OLT because of their supposed potential for alcoholic recidivism and poor compliance with the required immunosuppressive regimen, both of which result in graft failure. Only inconclusive data related to these arguments are available. From May 1982 to January 1993, 58 patients received OLT at our institution for end-stage cirrhosis, where alcohol was the only toxic component. The indication for OLT in these patients was considered with particular attention to recidivism and compliance. Overall survival in this group was 71% and 63% at 1 and 5 years, respectively, with an average survival time of 78 months. Actuarial survival of patients transplanted since January 1989 (n = 37) was 86% and 83% at 1 and 2 years (average survival 42 months). Nonfatal clinical endpoints were analyzed in those patients surviving at least 3 months (n = 44). Return to alcohol abuse has been documented in 14 persons at routine short-term outpatient checkups. The estimated risk for alcoholic recidivism amounts to 31%, with a median follow-up of 33 months. Compliance with immunosuppressive regimen was expressed as a dependent value of acute rejection episodes (0.3 per patient, median follow-up 33 months), chronic rejection (occurred in none of the patients), and measurements of CsA HPLC blood trough level (92.2% within the target range). The preversus postoperative improvement of employment, marital, and social status after OLT showed a statistically significant difference. Unwillingness to offer OLT to individuals with alcoholic liver disease because of failure to demonstrate 100% long-term abstinence appears difficult to defend in the face of good results in survival, compliance, and social rehabilitation.

Do we need HER-2/neu testing for all patients with primary breast carcinoma?

HER‐2/neu is a valuable prognostic marker in primary breast carcinoma. Controversy surrounds the correlation between HER‐2/neu expression and other prognostic markers, as has been discussed in preclinical and clinical studies. The objective of the current study was to investigate the probability, calculated using parameters that are assessed routinely in clinical practice, that patients with breast carcinoma had positive HER‐2/neu status.

The prevalence of hemorrhoids in adults

IntroductionExact data on the prevalence of hemorrhoids are rare. Therefore, we designed a study to investigate the prevalence of hemorrhoids and associated risk factors in an adult general population.MethodsBetween 2008 and 2009, consecutive patients were included in a prospective study. They attended the Austrian national wide health care program for colorectal cancer screening at four medical institutions. A flexible colonoscopy and detailed examination were conducted in all patients. Hemorrhoids were defined according to a standardized grading system. Independent variables included baseline characteristics, sociodemographic data, and health status. Potential risk factors were calculated by univariate and multivariate analysis.ResultsOf 976 participants, 380 patients (38.93%) suffered from hemorrhoids. In 277 patients (72.89%), hemorrhoids were classified as grade I, in 70 patients (18.42%) as grade II, in 31 patients (8.16%) as grade III, and in 2 patients (0.53%) as grade IV. One hundred seventy patients (44.74%) complained about symptoms associated with hemorrhoids, whereas 210 patients (55.26%) reported no symptoms. In the univariate and multivariate analysis, body mass index (BMI) had a significant effect on the occurrence of hemorrhoids with p = 0.0391 and p = 0.0282, respectively. Even when correcting for other potential risk factors, an increase in the BMI of one increased the risk of hemorrhoids by 3.5%.ConclusionHemorrhoids occur frequently in the adult general population. Notably, a considerable number of people with hemorrhoids do not complain about symptoms. In addition, a high BMI can be regarded as an independent risk factor for hemorrhoids.

Radical Surgical Therapy of Abdominal Cystic Hydatid Disease: Factors of Recurrence

Abstract. A series of 74 consecutive patients (48 women, 26 men) were operated for abdominal hydatid disease between June 1949 and December 1995. The patients ranged in age from 15 to 81 years (median 49 years). In 69 cases only the liver was affected; two patients had concomitant extrahepatic disease (one spleen, one spleen and lung), and 3 had cysts in the spleen only. Cysts were multiple in 11 patients and calcified in 24. Conservative surgical procedures were used for 22 cysts in 20 patients [open partial (n= 3), open total (n= 6), closed total cystectomy (n= 9), marsupialization (n= 2), drainage (n= 2)] and radical surgical procedures for 72 cysts in 54 patients [pericystectomy (n= 41), wedge liver resection or hemihepatectomy (n= 25), splenectomy (n= 5), radical resection of a lung cyst (n= 1)]. Altogether 37 patients (50%) were given perioperative antihelmintic chemotherapy with mebendazole (18 patients) or albendazole (19 patients). Operative mortality rates were 5.0% after conservative surgery and 1.8% after radical surgery. Morbidity rates were 25.0% following conservative surgery and 24.1% following radical surgery. Antihelmintic therapy was well tolerated by all but five patients. All side effects were entirely reversible. Among the 74 patients, 60 (81.0%) were available for long-term follow-up (median 7.2 years; range 2.0–47.0 years). Recurrence of disease was seen in 9 of 60 patients at an interval of 3 months to 20 years from the first operation. The rate of recurrence was significantly lower after radical surgical procedures (p= 0.03) and after closed removal of the cyst (p= 0.04).

Attenuation of catecholamine-induced immunosuppression in whole blood from patients with sepsis.

Studies performed on healthy volunteers have revealed that catecholamines down-regulate the lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)alpha, interleukin (IL)-6, and IL-1beta. We extended this observation and show that this effect is based on changes in the mRNA concentration of these cytokines. Catecholamines are increased in severe sepsis due to endogenous production and have to be administered exogenously when the disease has proceeded to the state of prolonged hypotension. We here investigated whether the immunomodulating effect of catecholamines could also be demonstrated in the blood of patients with prolonged severe sepsis and of those in prolonged septic shock. Blood was stimulated ex vivo with LPS in the presence and absence of epinephrine and the cytokine protein concentration was determined. In blood of healthy volunteers, epinephrine reduced the LPS-stimulated synthesis of TNFalpha by 62.5% (P< 0.0001), of IL-6 by 39% (P< 0.0001), and of IL-1beta by 40% (P= 0.015), and increased the LPS-stimulated IL-10 production by 77.8% (P < 0.0001). Correspondingly, in blood of patients with prolonged severe sepsis, TNFalpha was reduced by 67.2% (P < 0.0001) and IL-6 was reduced by 32.9% (P < 0.0001); IL-1beta and IL-10 were not modulated by catecholamines in these patients. In blood samples of patients in prolonged septic shock, epinephrine did not modulate cytokine levels of IL-6 and IL-10, and decreased TNFalpha only by 36.4% (P < 0.0001). Interestingly, epinephrine suppressed the IL-1beta production by 73% (P < 0.0001) in blood of patients in prolonged septic shock, which was twice as much as in blood samples of healthy volunteers. The altered response of septic blood to catecholamines might be due to an altered reactivity of leukocytes in the prolonged disease although an additional role of preexisting catecholamines cannot be completely excluded.

Evaluation of perianal sepsis: Comparison of anal endosonography and magnetic resonance imaging

The purpose of this study was to compare prospectively the diagnostic yield of anal endosonography (AES) and magnetic resonance imaging (MRI) in the assessment of perianal fistulae and abscesses. There were 39 patients (14 men, 25 women; mean age, 40 years) who underwent AES, performed with a 10‐MHz rotating endoanal probe and MRI at 1.0 T (axial and coronal T2‐weighted turbo spin‐echo (TSE) and turbo‐STIR sequences). Fistulae were classified as subcutaneous, intersphincteric, transsphincteric, high (i.e., high extrasphincteric or suprasphincteric), rectovaginal, and horseshoe and were compared with the surgical findings in all patients. Overall, 58 fistulae (subcutaneous, N = 7; intersphincteric, N = 9; transsphincteric, N = 16; high, N = 17; rectovaginal, N = 5; and horseshoe, N = 4) were detected at surgery. MRI showed a sensitivity of 84% and AES of 60% (P < .05). False‐positive diagnoses were made in 6 patients (15%) with MRI and in 15 patients (26%) with AES, for a specificity of 68% and 21%, respectively (P < .05). Our findings show that MRI is superior to AES in the assessment of fistula‐in‐ano before major surgery. AES should be used only for orientation before minor procedures, such as incision or drainage of subcutaneous fistulae. J. Magn. Reson. Imaging 2001;14:254–260.

Functional and morphometric evaluation of end-to-side neurorrhaphy for muscle reinnervation.

This study was undertaken to quantify the effect of motor collateral sprouting in an end-to-side repair model allowing end organ contact. Besides documentation of the functional outcome of muscle reinnervation by end-to-side neurorrhaphy, this experimental work was performed to determine possible downgrading effects to the donor nerve at end organ level. In 24 female New Zealand White rabbits, the motor nerve branch to the rectus femoris muscle of the right hindlimb was dissected, cut, and sutured end-to-side to the motor branch to the vastus medialis muscle after creating an epineural window. The 24 rabbits were divided into two groups of 12 each, with the second group receiving additional crush injury of the vastus branch. After a period of 8 months, maximum tetanic tension in the reinnervated rectus femoris and the vastus medialis muscles was determined. The contralateral healthy side served as control. The reinnervated rectus femoris muscle showed an average maximum tetanic force of 24.9 N (control 26.2 N, p = 0.7827), and the donor vastus medialis muscle 11.0 N (control 7.3 N, p = 0.0223). There were no statistically significant differences between the two experimental groups (p = 0.9914). The average number of regenerated myelinated nerve fibers in the rectus femoris motor branch was 1185 ± 342 (control, 806 ± 166), and the mean diameter was 4.6 ± 0.6 &mgr;m (control, 9.4 ± 1.0 &mgr;m). In the motor branch to the vastus medialis muscle, the mean fiber number proximal to the coaptation site was 1227 (±441), and decreased distal to the coaptation site to 795 (±270). The average difference of axon counts in the donor nerve proximal to distal regarding the repair site was 483.7 ± 264.2. In the contralateral motor branch to the vastus medialis muscle, 540 (±175) myelinated nerve fibers were counted. In nearly all cross-section specimens of the motor branch to the vastus medialis muscle, altered nerve fibers could be identified in one fascicle distal and proximal to the repair site. The results show a relevant functional reinnervation by end-to-side neurorrhaphy without functional impairment of the donor muscle. It seems to be evident that most axons in the attached segment were derived from collateral sprouts. Nonetheless, the present study confirms that end-to-side neurorrhaphy is a reliable method of reconstruction for damaged nerves, which should be applied clinically in a more extended manner. (Plast. Reconstr. Surg. 106: 383, 2000.)

Pseudo R-squared measures for Poisson regression models with over- or underdispersion

The Poisson regression model is frequently used to analyze count data. Pseudo R-squared measures for Poisson regression models have recently been proposed and bias adjustments recommended in the presence of small samples and/or a large number of covariates. In practice, however, data are often over- or sometimes even underdispersed as compared to the standard Poisson model. The definition of Poisson R-squared measures can be applied in these situations as well, albeit with bias adjustments accordingly adapted. These adjustments are motivated by arguments of quasi-likelihood theory. Properties of unadjusted and adjusted R-squared measures are studied by simulation under standard Poisson; over- and underdispersed Poisson regression models and their use is exemplified and discussed with popcorn data.