Effect of concomitant statin treatment in postmenopausal patients with hormone receptor-positive early-stage breast cancer receiving adjuvant denosumab or placebo: a post hoc analysis of ABCSG-18.

BACKGROUND: Statins are cholesterol-lowering drugs prescribed for the prevention and treatment of cardiovascular disease. Moreover, statins may possess anticancer properties and interact with receptor activator of nuclear factor κB ligand expression. We aimed at evaluating a hypothetical synergistic effect of statins with denosumab in early-stage breast cancer (BC) patients from the Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 18. PATIENTS AND METHODS: ABCSG-18 (NCT00556374) is a prospective, randomized, double-blind, phase III study; postmenopausal patients with hormone receptor-positive BC receiving a nonsteroidal aromatase inhibitor were randomly assigned to denosumab or placebo. In this post hoc analysis, we investigated the effects of concomitant statin therapy on recurrence risk (RR) of BC, fracture risk and bone mineral density (BMD). RESULTS: In the study population (n = 3420), statin therapy (n = 824) was associated with worse disease-free survival (DFS) [hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.04-1.75; P = 0.023]. While no significant effect of lipophilic statins (n = 710) on RR was observed (HR 1.30, 95% CI 0.99-1.72; P = 0.062), patients on hydrophilic statins (n = 87) had worse DFS compared with patients not receiving any statins (HR 2.00, 95% CI 1.09-3.66; P = 0.026). This finding was mainly driven by the effect of hydrophilic statins on DFS in the denosumab arm (HR 2.63, 95% CI 1.21-5.68; P = 0.014). However, this effect subsided after correction for confounders in the sensitivity analysis. No association between statin use and fracture risk or osteoporosis was observed. CONCLUSION: According to this analysis, hydrophilic statins showed a detrimental effect on DFS in the main model, which was attenuated after correction for confounders. Our data need to be interpreted with caution due to their retrospective nature and the low number of patients receiving hydrophilic statins.

Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study.

BACKGROUND: High-risk triple-negative breast cancers (TNBCs) are characterized by poor prognosis, rapid progression to metastatic stage and onset of resistance to chemotherapy, thus representing an area in need of new therapeutic approaches. Programmed death-ligand 1 (PD-L1) expression is an adaptive mechanism of tumour resistance to tumour-infiltrating lymphocytes, which in turn are needed for response to chemotherapy. Overall, available data support the concept that blockade of PD-L1/programmed cell death protein 1 checkpoint may improve efficacy of classical chemotherapy. PATIENTS AND METHODS: Two hundred and eighty patients with TNBC were enrolled in this multicentre study (NCT002620280) and randomized to neoadjuvant carboplatin area under the curve 2 and nab-paclitaxel 125 mg/m2 intravenously (i.v.) on days 1 and 8, without (n = 142) or with (n = 138) atezolizumab 1200 mg i.v. on day 1. Both regimens were given q3 weeks for eight cycles before surgery followed by four cycles of an adjuvant anthracycline regimen. The primary aim of the study was to compare event-free survival (EFS), and an important secondary aim was the rate of pathological complete response (pCR defined as the absence of invasive cells in breast and lymph nodes). The primary population for all efficacy endpoints is the intention-to-treat (ITT) population. RESULTS: The ITT analysis revealed that pCR rate after treatment with atezolizumab (48.6%) did not reach statistical significance compared to no atezolizumab [44.4%: odds ratio (OR) 1.18; 95% confidence interval 0.74-1.89; P = 0.48]. Treatment-related adverse events were similar with either regimen except for a significantly higher overall incidence of serious adverse events and liver transaminase abnormalities with atezolizumab. CONCLUSIONS: The addition of atezolizumab to nab-paclitaxel and carboplatin did not significantly increase the rate of pCR in women with TNBC. In multivariate analysis, the presence of PD-L1 expression was the most significant factor influencing the rate of pCR (OR 2.08). Continuing follow-up for the EFS is ongoing, and molecular studies are under way.

A clinical validation study of MammaPrint in hormone receptor-positive breast cancer from the Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG-8) biomarker cohort.

BACKGROUND: MammaPrint is a prognostic assay based on gene expression in tumors from patients with early breast cancer. MammaPrint has been extensively validated and Food and Drug Administration cleared in fresh and formalin-fixed and paraffin-embedded (FFPE) tissue. We aimed to assess its prognostic performance in the biomarker cohort of the Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG-8) patient population, and to obtain a higher level of evidence with regard to its clinical validity after RNA extraction from FFPE biobank tissue. PATIENTS AND METHODS: A prespecified retrospective analysis to test the prognostic performance of the MammaPrint test to predict distant recurrence-free survival at 5 and 10 years as primary end point was carried out. MammaPrint risk, clinicopathological factors (after central pathological review), and clinical risk (using a modified version of Adjuvant! Online) were evaluated by Cox regression analyses. RESULTS: From 1347 available samples, 607 (45%) failed quality control after RNA extraction. In total, 658 (49%) patients were included in survival analyses: MammaPrint low risk versus high risk is a significant prognostic factor for distant recurrence-free survival at 5 years (94.0% versus 91.6%) with a significant risk reduction of 6.5% at 10 years (log-rank P value = 0.017, low risk 91.3% versus high risk 84.8%). The multivariable models suggest that hazard ratio (HR) is primarily driven by tumor stage (5-year HR 3.89; confidence interval 1.97-7.71) and nodal status (5-year HR 1.73; confidence interval 0.91-3.21). After adjustment for clinical risk groups, MammaPrint HRs remain stable with values just below 2.0 after the first 3 years. CONCLUSIONS: The MammaPrint test showed significant prognostic performance at 5 and 10 years of follow-up. In the particular cohort of ABCSG-8, the statistical independence from clinically assessed covariates remains unclear, and no conclusions concerning the clinical validity of the test can be drawn.

Primary surgery versus no surgery in synchronous metastatic breast cancer: patient-reported quality-of-life outcomes of the prospective randomized multicenter ABCSG-28 Posytive Trial.

BACKGROUND: The ABCSG-28 trial compared primary surgery followed by systemic therapy versus primary systemic therapy without surgery in patients with de novo stage IV BC. The present report describes QoL results of this trial. METHODS: Ninety patients with primary operable MBC were randomised to surgery of the primary tumor followed by systemic therapy or to primary systemic therapy without surgery. QoL analyses covering the results at baseline, 6,12,18 and 24 months follow up of 79 (88%) patients, was assessed with the EORTC QLQ-C30 and QLQ-BR23 questionnaires. RESULTS: There were no statistically significant differences in any of the scales of the QLQ-C30 and QLQ-BR23 questionnaires between the two groups over the time. Baseline global health status and physical functioning were predictors for OS (patients with a higher score lived longer (p=0.0250, p=0.0225; p=0.0355, p=0.0355)). Global health status, social functioning scale, breast symptoms and future perspective were predictors for longer TTPd (p=0.0244; p=0.0140, p=0.020; p=0.0438, p=0.0123). Patients in both arms reported significant improvement on the emotional functioning scale. Cognitive functioning decreased over time in both groups. Younger women had clinically relevant better physical and sexual functioning scores (p=0.039 and 0.024). CONCLUSION: Primary surgery does not improve nor alter QoL of patients with de novo stage IV BC. Global health status and physical functioning were predictors for OS and could be use as additional marker for prediction of OS and TTTd in patients with de novo stage IV BC. TRIAL REGISTRATION: The trial is registered on clinicaltrial.gov (NCT01015625, date of registration:18/11/2009).

Time trends (2006-2015) of quality indicators in EUSOMA-certified breast centres.

AIM OF THE STUDY: The European Society of Breast Cancer Specialists (EUSOMA) has fostered a voluntary certification process for breast centres to establish minimum standards and ensure specialist multidisciplinary care. Prospectively collected anonymous information on primary breast cancer cases diagnosed and treated in the units is transferred annually to a central EUSOMA data warehouse for continuous monitoring of quality indicators (QIs) to improve quality of care. Units have to comply with the EUSOMA Breast Centre guidelines and are audited by peers. The database was started in 2006 and includes over 110,000 cancers from breast centres located in Germany, Switzerland, Belgium, Austria, The Netherlands, Spain, Portugal and Italy. The aim of the present study is assessing time trends of QIs in EUSOMA-certified breast centres over the decade 2006-2015. MATERIALS AND METHODS: Previously defined QIs were calculated for 22 EUSOMA-certified breast centres (46122 patients) during 2006-2015. RESULTS: On the average of all units, the minimum standard of care was achieved in 8 of 13 main EUSOMA QIs in 2006 and in all in 2015. All QIs, except removal of at least 10 lymph nodes at axillary clearance and oestrogen receptor-negative tumours (T > 1 cm or N+) receiving adjuvant chemotherapy, improved significantly in this period. The desirable target was reached for two QIs in 2006 and for 7 of 13 QIs in 2015. CONCLUSION: The EUSOMA model of audit and monitoring QIs functions well in different European health systems and results in better performance of QIs over the last decade. QIs should be evaluated and adapted on a regular basis, as guidelines change over time.

Elevated mRNA expression of CHAC1 splicing variants is associated with poor outcome for breast and ovarian cancer patients.

BACKGROUND: The role of CHAC1 (cation transport regulator-like protein 1), a recently identified component of the unfolded protein response (UPR) pathway, in gynaecological cancers has not yet been characterised. Now, this work illustrates CHAC1 mRNA expression and associated clinical outcome in breast and ovarian cancer. METHODS: The prognostic value of CHAC1 and its two transcript variants was investigated in 116 breast and 133 ovarian tissues using quantitative real-time reverse-transcriptase PCR. Subsequently, we conducted functional studies using short-interfering RNA-mediated knockdown and plasmid-mediated overexpression of CHAC1 in breast and ovarian cancer cells. RESULTS: Poorly differentiated tumours exhibited higher CHAC1 mRNA expression (breast cancer: P=0.004; ovarian cancer: P=0.024). Hormone receptor-negative breast tumours and advanced-staged ovarian cancers demonstrated elevated CHAC1 mRNA expression levels (P<0.001 and P=0.026, respectively). The multivariate survival analysis showed a prognostic value of both transcript variants in breast cancer (transcript variant 1: RR(death) 6.7 (2.4-18.9); P<0.001), RR(relapse) 6.7 (2.1-21.3); P=0.001); (transcript variant 2: RR(death) 4.9 (2.0-12.4); P<0.001), RR(relapse) 8.0 (2.4-26.8); P<0.001). Ovarian cancer patients aged younger than 62.6 years with high CHAC1 mRNA expression showed poorer relapse-free- and overall-survival (P=0.030 and P=0.012, respectively). In functional studies CHAC1 knockdown suppressed cell migration, whereas ectopic overexpression opposed these effects. CONCLUSION: High CHAC1 mRNA expression could be an independent indicator for elevated risk of cancer recurrence in breast and ovarian cancer.

Appearance of the fetal posterior fossa at 11 + 3 to 13 + 6 gestational weeks on transabdominal ultrasound examination.

OBJECTIVES: To describe the sonographic appearance of the structures of the posterior cranial fossa in fetuses at 11 + 3 to 13 + 6 weeks of pregnancy and to determine whether abnormal findings of the brain and spine can be detected by sonography at this time. METHODS: This was a prospective study including 692 fetuses whose mothers attended Innsbruck Medical University Hospital for first-trimester sonography. In 3% (n = 21) of cases, measurement was prevented by fetal position. Of the remaining 671 cases, in 604 there was either a normal anomaly scan at 20 weeks or delivery of a healthy child and in these cases the transcerebellar diameter (TCD) and the anteroposterior diameter of the cisterna magna (CM), measured at 11 + 3 to 13 + 6 weeks, were analyzed. In 502 fetuses, the anteroposterior diameter of the fourth ventricle (4V) was also measured. In 25 fetuses, intra- and interobserver repeatability was calculated. RESULTS: We observed a linear correlation between crown-rump length (CRL) and CM (CM = 0.0536 × CRL - 1.4701; R2 = 0.688), TCD (TCD = 0.1482 × CRL - 1.2083; R2 = 0.701) and 4V (4V = 0.0181 × CRL + 0.9186; R2 = 0.118). In three patients with posterior fossa cysts, measurements significantly exceeded the reference values. One fetus with spina bifida had an obliterated CM and the posterior border of the 4V could not be visualized. CONCLUSIONS: Transabdominal sonographic assessment of the posterior fossa is feasible in the first trimester. Measurements of the 4V, the CM and the TCD performed at this time are reliable. The established reference values assist in detecting fetal anomalies. However, findings must be interpreted carefully, as some supposed malformations might be merely delayed development of brain structures.

Impact of nuchal cord on measurement of fetal nuchal translucency thickness.

OBJECTIVE: To define the impact of nuchal cord on the measurement of fetal nuchal translucency thickness (NT). METHODS: Between December 2004 and June 2006, we examined prospectively 53 fetuses that were observed on routine first-trimester ultrasound examination between 11 + 3 and 13 + 6 weeks of gestation to have nuchal cord causing an indentation in the skin in the nuchal region. The fetuses were re-examined after a median interval of 132 min, when the cord was no longer around the neck and indentation of the skin had resolved. Various NT measurements (highest, lowest, mean) with the cord located around the neck (nuchal cord) were compared with NT measurements in the absence of nuchal cord ('true' NT) in the same fetuses. Measurements were considered to be equal when they were within mean +/- 1.96 SD, defined by our own intraobserver repeatability according to the method of Bland and Altman. RESULTS: The mean of the largest and the smallest of six measurements in the presence of nuchal cord fell within the mean +/- 1.96 SD of our own intraobserver repeatability, i.e. gave a correct estimate of the true NT, in 80% of fetuses, while the NT was overestimated in 10% and underestimated in 10% of fetuses. The largest and the smallest of six measurements in the presence of nuchal cord gave an underestimate of the true NT in 2% of fetuses and an overestimate in 4% of fetuses, respectively. CONCLUSION: There is a wide scattering of measurements in fetuses with nuchal cord in comparison to the same fetuses in the absence of nuchal cord. This prevents accurate prediction of the true NT, although the largest and smallest of repeat measurements with nuchal cord can allow calculation of the highest and lowest possible risks, respectively. These facts must be taken into consideration in counseling patients.

Functional granulocyte/macrophage colony stimulating factor receptor is constitutively expressed on neoplastic plasma cells and mediates tumour cell longevity.

It has been shown that granulocyte/macrophage colony stimulating factor (GM-CSF) is able to support myeloma cell propagation in cooperation with interleukin (IL)-6, the major growth factor for malignant plasma cells, although the biological mechanisms involved remain unknown. Therefore we investigated (i) the expression levels of the GM-CSF receptor (GM-CSFR) constituents in three malignant plasma cell lines and in native malignant plasma cells, (ii) the ability of the receptor to mediate common signalling pathways regulating proliferation and cell survival in malignant plasma cell lines, and (iii) the effects of GM-CSF on tumour cell biology. The GM-CSFRalpha subunit was detected in the malignant plasma cell lines RPMI-8226, MC/CAR, IM-9 as well as 6/6 native myeloma cell samples derived from the bone marrow of patients with overt disease. Furthermore, GM-CSFR expression was also detected in the CD19+ fraction from 2/3 bone marrow samples and 5/8 peripheral blood samples derived from patients with malignant plasma cell disorders, but not in the CD19+ fraction of peripheral blood from healthy donors. The expressed cytokine receptor alpha-subunit was able to constitute a functional signalling complex with the ubiquitously expressed GM-CSFRbeta subunit, as demonstrated by the fact that GM-CSF induced the p21-ras/mitogen-activated protein kinase (MAPK) signalling cascade in malignant plasma cell lines. Since this signalling cascade plays an essential role in the mediation of both proliferation and cell survival, we investigated the impact of GM-CSF on these two events. Application of GM-CSF led to an increase of DNA-synthesis in MC/CAR, IM-9 and RPMI-8226 cells. Furthermore, it increased longevity of these malignant plasma cell lines by reducing the rates of spontaneous apoptosis. We conclude that (i) the functional GM-CSFR is commonly expressed on malignant plasma cells and that (ii) GM-CSF promotes the clonal expansion of myeloma cells by inhibiting spontaneous apoptosis and promoting DNA synthesis.

Strength of ACL reconstructions using semitendinosus tendon grafts.

PURPOSE: Patellar tendon autografts have been considered by many as the gold standard for intraarticular reconstruction of the anterior cruciate ligament (ACL). Hamstring tendon grafts are being used increasingly, however there are few studies focusing on their mechanical properties. The objectives of the present study are to determine the strength of a semitendinosus graft at various postoperative periods. METHODS: In Part I of the study, a looped semitendinosus graft was used to reconstruct the ACL in five frozen human cadaver knees with a simulated endoscopic technique. The immediate post-operative strength was determined by loading the knees of failure using a mechanical testing system. In Part II the effects of graft maturation and incorporation were considered. A similar graft was used to reconstruct the ACL in twelve ewe sheep. Their knees were harvested and tested at four, eight, and twelve weeks postoperatively. RESULTS: The mean maximum strength and stiffness of the cadaveric reconstructions were 352 N and 8.18 N/mm, respectively. All failures occurred at the fixation sites. The average strength of the sheep reconstructions was similar at four, eight, and twelve weeks (376 N. 415 N. and 323 N. respectively). The stiffness increased from 21.1 N/mm at four weeks to 46.7 N/mm at eight weeks and then remained the same. The failures occurred primarily by tendon pull-out of the femoral tunnel at four, eight and twelve weeks. CONCLUSIONS: Graft pull-out from the femoral tunnel implies incomplete tendon incorporation during the initial three months post-operatively. Activities which place high loads on the graft should be avoided during this period. Additionally, the mechanical properties of this hamstring graft reconstruction are similar to those reported for patellar tendon grafts in other animal models.

Analysis of a semitendinosus autograft in a rabbit model.

The purpose of this study was to evaluate the histologic and biomechanical changes that occur between 12 and 52 weeks in an intraarticular, semitendinosus autograft placed through tibial and femoral drill holes in a rabbit model. The results of this study show that, in this rabbit model, the soft tissue graft maintained its biologic fixation in the osseous tunnel when stressed to failure at 1 year. The bony fixation occurred by the formation of an indirect tendon insertion, and this formation was complete by 26 weeks. At 52 weeks, large differences persisted in the strength and stiffness of the graft compared with the normal semitendinosus tendon and anterior cruciate ligament. Based on the results of this study, we support a cautious approach in returning patients to early full activity, including sports, after anterior cruciate ligament reconstruction with a semitendinosus autograft.

Biomechanical effects of gamma irradiation on fresh frozen allografts in vivo.

The effect of gamma irradiation on the mechanical properties of allograft in a rabbit model was examined. Tibial allografts were tested in torsion to failure to determine maximum torque and maximum stress. Statistically significant degradation in the torsional strength of irradiated tibias vs controls was demonstrated. Femoral allografts were orthotopically implanted into experimental rabbits and secured with an intramedullary pin. Rates of incorporation and failure patterns were significantly altered by irradiation. These data suggest that sterilization of fresh-frozen allografts with 2.5 Mrad or greater severely degrades the ability of the graft to resist torsion. The rate of incorporation of fresh-frozen allografts also may be dramatically decreased as a result of irradiation.

Ligamentous and tendinous support of the pisiform: anatomic and biomechanical study.

Twenty-five formalin-preserved cadaveric wrists were dissected and the relationship of the pisotriquetral joint (PTJ) and its surrounding soft tissue structures were defined. An additional 4 fresh frozen wrists were examined in longitudinal and transverse sections. These anatomical studies showed the extensor retinaculum to have a complex insertion into the pisiform, flexor carpi ulnaris, fifth metacarpal, pisometacarpal ligament, and the abductor digiti minimi muscle. A capsuloligamentous structure on the medial aspect of the pisotriquetral joint was also identified. Biomechanical testing was performed on 12 fresh cadaver wrists and the results were compared to the anatomical findings to determine the contribution of surrounding soft tissue structures to pisotriquetral joint stability. Mechanical testing showed the soft tissues around the pisotriquetral joint to be strongest proximally and distally and weakest medially. Transection of the transverse carpal ligament resulted in increased lateral motion of the pisiform, but there was no significant decrease in stiffness. This study provides insight into the etiology of pisotriquetral joint instability and dysfunction.

The effects of anabolic steroids on rat tendon. An ultrastructural, biomechanical, and biochemical analysis.

Forty-eight male rats were randomly separated into four groups: a control group, a group treated with anabolic steroids, a group treated with daily exercise, and a group treated with both steroids and exercise. At 6 weeks, biomechanical, ultrastructural, and biochemical testing was performed on the Achilles tendons of half of the rats in each group. The remaining rats continued in the experimental protocol, but steroid administration was discontinued. Similar testing was then performed on the remaining rats at 12 weeks. Testing showed anabolic steroids produced a stiffer tendon that absorbs less energy and fails with less elongation; tendon strength was unaffected. Effects were entirely reversible on discontinuation of the steroids. Light microscopic analysis revealed no changes in the appearance of the fibrils. No change in fibril diameter or shape was noted on electron microscopic analysis. Biochemical testing revealed no change in qualitative immunofluorescence staining with Type III collagen or fibronectin. Abuse of anabolic steroids is a widespread problem among competitive athletes; consequently, complications after their use are seen with increasing frequency. Knowledge of the effects of these drugs on tendon and the musculotendinous unit may prove helpful in counseling athletes who use anabolic steroids.

Ligamentous and tendinous support of the pisiform, anatomic and biomechanical study.

Twenty-five formalin preserved cadaveric wrists were dissected and the relationship of the piso-triquetral joint and its surrounding soft tissue structures were defined. An additional 4 fresh frozen wrists were examined in longitudinal and transverse sections. These anatomical studies showed the extensor retinaculum to have a complex insertion into the pisiform, flexor carpi ulnaris, fifth metacarpal, piso-metacarpal ligament, and the abductor digit minimi muscle. A capsulo-ligamentous structure on the medial aspect of the piso-triquetral joint was also identified. Bio-mechanical testing was performed on 12 fresh cadaver wrists and the results were compared to the anatomical findings to determine the contribution of surrounding soft tissue structures to piso-triquetral joint stability. Mechanical testing showed the soft tissues around the piso-triquetral joint to be strongest proximally and distally and weakest medially. Transection of the transverse carpal ligament resulted in increased lateral motion of the pisiform, but there was no significant decrease in stiffness. This study provides insight into the etiology of piso-triquetral joint instability and dysfunction.

An analysis of autograft fixation after anterior cruciate ligament reconstruction in a rabbit model.

Fixation and incorporation of a tendon implanted within the bone pose theoretical as well as practical concerns for the surgeon who treats instability problems of the knee. Understanding the physiology involved in graft-bone incorporation is necessary for the appropriate rehabilitation of patients who undergo anterior cruciate ligament surgery. The purpose of the study was to examine the histologic and biomechanical changes of a semitendinosus autograft reconstruction of the anterior cruciate ligament in a rabbit model at the graft-bone tunnel interface in the femur. The results indicate that by 3 weeks, failure of the bone-graft-bone or construction is through the intraarticular portion of the graft, not as a result of pullout from the bone tunnel. Graft fixation of the bone tunnel occurs by an intertwining of graft and connective tissue and anchoring of connective tissue to bone by collagenous fibers and bone formation in the tunnels. The collagenous fibers have the appearance of the Sharpey's fibers seen in an indirect tendon insertion.

The effect of anabolic steroids on the biomechanical and histological properties of rat tendon.

Twenty-four male rats were divided into four groups, with anabolic steroids and exercise as variables. Biomechanical tests and histological evaluations were performed. The results of the biomechanical tests suggested that anabolic steroids produce a stiffer tendon, which fails with less elongation. The energy at the time when the tendon failed, the toe-limit elongation, and the elongation at the time of the first failure were all affected significantly. Changes in the force at failure were not statistically significant. No alterations of structure were noted when the specimens were viewed with light microscopy. Alterations of the sizes of the collagen fibrils were noted on electron microscopy.