Fragility fractures – Global call to action Dreinhöfer, Karsten E.
Best practice & research. Clinical rheumatology,
April 2019, 2019-04-00, 20190401, Letnik:
33, Številka:
2
Journal Article
Tumour-infiltrating lymphocytes (TILs) are predictive for response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) and HER2-positive breast cancer, but their role in luminal ...breast cancer and the effect of TILs on prognosis in all subtypes is less clear. Here, we assessed the relevance of TILs for chemotherapy response and prognosis in patients with TNBC, HER2-positive breast cancer, and luminal–HER2-negative breast cancer.
Patients with primary breast cancer who were treated with neoadjuvant combination chemotherapy were included from six randomised trials done by the German Breast Cancer Group. Pretherapeutic core biopsies from 3771 patients included in these studies were assessed for the number of stromal TILs by standardised methods according to the guidelines of the International TIL working group. TILs were analysed both as a continuous parameter and in three predefined groups of low (0–10% immune cells in stromal tissue within the tumour), intermediate (11–59%), and high TILs (≥60%). We used these data in univariable and multivariable statistical models to assess the association between TIL concentration and pathological complete response in all patients, and between the amount of TILs and disease-free survival and overall survival in 2560 patients from five of the six clinical trial cohorts.
In the luminal–HER2-negative breast cancer subtype, a pathological complete response (pCR) was achieved in 45 (6%) of 759 patients with low TILs, 48 (11%) of 435 with intermediate TILs, and 49 (28%) of 172 with high TILs. In the HER2-positive subtype, pCR was observed in 194 (32%) of 605 patients with low TILs, 198 (39%) of 512 with intermediate TILs, and 127 (48%) of 262 with high TILs. Finally, in the TNBC subtype, pCR was achieved in 80 (31%) of 260 patients with low TILs, 117 (31%) of 373 with intermediate TILs, and 136 (50%) of 273 with high TILs (p<0·0001 for each subtype, χ2 test for trend). In the univariable analysis, a 10% increase in TILs was associated with longer disease-free survival in TNBC (hazard ratio HR 0·93 95% CI 0·87–0·98, p=0·011) and HER2-positive breast cancer (0·94 0·89–0·99, p=0·017), but not in luminal–HER2-negative tumours (1·02 0·96–1·09, p=0·46). The increase in TILs was also associated with longer overall survival in TNBC (0·92 0·86–0·99, p=0·032), but had no association in HER2-positive breast cancer (0·94 0·86–1·02, p=0·11), and was associated with shorter overall survival in luminal–HER2-negative tumours (1·10 1·02–1·19, p=0·011).
Increased TIL concentration predicted response to neoadjuvant chemotherapy in all molecular subtypes assessed, and was also associated with a survival benefit in HER2-positive breast cancer and TNBC. By contrast, increased TILs were an adverse prognostic factor for survival in luminal–HER2-negative breast cancer, suggesting a different biology of the immunological infiltrate in this subtype. Our data support the hypothesis that breast cancer is immunogenic and might be targetable by immune-modulating therapies. In light of the results in luminal breast cancer, further research investigating the interaction of the immune system with different types of endocrine therapy is warranted.
Deutsche Krebshilfe and European Commission.
The profile of human health is changing across the globe such that the burden of noncommunicable diseases (NCDs), particularly musculoskeletal conditions, is becoming more profound. Such change ...demands that health systems adapt to better support people in maintaining a functional health state and quality of life, as life expectancy continues to increase. In parallel to the rising burden of NCDs, in particular a disability burden, the need for rehabilitation services is increasing. The World Health Organization (WHO) responded recently with "Rehabilitation 2030: A Call for Action" (February 6-7, 2017, Geneva, Switzerland) and the publication of key recommendations for action. In this editorial, the authors reflect on Rehabilitation 2030 and consider its implications for health system reform in the context of rehabilitation for musculoskeletal health. J Orthop Sports Phys Ther 2017;47(5)297-300. doi:10.2519/jospt.2017.0105.
According to current guidelines, molecular tests predicting the outcome of breast cancer patients can be used to assist in making treatment decisions after consideration of conventional markers. We ...developed and validated a gene expression signature predicting the likelihood of distant recurrence in patients with estrogen receptor (ER)-positive, HER2-negative breast cancer treated with adjuvant endocrine therapy.
RNA levels assessed by quantitative reverse transcriptase PCR in formalin-fixed, paraffin-embedded tumor tissue were used to calculate a risk score (Endopredict, EP) consisting of eight cancer-related and three reference genes. EP was combined with nodal status and tumor size into a comprehensive risk score, EPclin. Both prespecified risk scores including cutoff values to determine a risk group for each patient (low and high) were validated independently in patients from two large randomized phase III trials Austrian Breast and Colorectal Cancer Study Group (ABCSG)-6: n = 378, ABCSG-8: n = 1,324.
In both validation cohorts, continuous EP was an independent predictor of distant recurrence in multivariate analysis (ABCSG-6: P = 0.010, ABCSG-8: P < 0.001). Combining Adjuvant!Online, quantitative ER, Ki67, and treatment with EP yielded a prognostic power significantly superior to the clinicopathologic factors alone c-indices: 0.764 vs. 0.750, P = 0.024 (ABCSG-6) and 0.726 vs. 0.701, P = 0.003 (ABCSG-8). EPclin had c-indices of 0.788 and 0.732 and resulted in 10-year distant recurrence rates of 4% and 4% in EPclin low-risk and 28% and 22% in EPclin high-risk patients in ABCSG-6 (P < 0.001) and ABCSG-8 (P < 0.001), respectively.
The multigene EP risk score provided additional prognostic information to the risk of distant recurrence of breast cancer patients, independent from clinicopathologic parameters. The EPclin score outperformed all conventional clinicopathologic risk factors.
There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing ...for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group.
The study comprised 802 women (median age 40 years, range 19-76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation.
A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20-29 years compared to 6.9% in the age group 60-69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50-2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years.
Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.
•Cytokine concentration in finger-prick blood VAMS was more variable than in venous.•Room temperature had the most significant changes in concentration over time.•The optimal storage temperature ...differed for each analyte.•Incomplete extraction of 6 spiked cytokines may indicate cytokine-VAMS interaction.
Dried blood spots (DBS) collected on filter paper such as Guthrie cards are stored for years at room temperature. The assumption is that once dried, the samples remain stable and quantifiable indefinitely since the metabolites these were initially designed to measure, are known for their extended stability. The concentration of other blood proteins such as cytokines, however, are known to vary with storage even in liquid samples stored at −80 °C for extended periods of time. We sought to determine if cytokines are stable for up to 5 months when stored as a dried blood sample using volumetric absorptive microsampling (VAMS) devices.
To test this, blood was collected from 4 healthy participants, spiked with recombinant cytokines, and collected into 30 µL VAMS devices. These prepared VAMS devices were stored at room temperature, 4 °C, or −20 °C for up to 5 months and matching VAMS liquid extracts were stored at −80 °C for the same period of time. At each timepoint, the samples were extracted from the VAMS devices and the extracts were analysed by Luminex® for quantification of up to 31 cytokines. These methods were also tested in a remote clinical study over a period of up to 8 months.
Cytokine analysis revealed that room temperature, the current standard for DBS and VAMS storage, performed the poorest out of all storage temperatures with significant losses in 13/21 analytes compared to 4 °C at 5 months. Storage at 4 °C or colder performed well for the majority of analytes tested, however out of those, the optimal storage temperature differed for each analyte. There were a small number of analytes that performed poorly regardless of storage conditions and for fractalkine, this was found to be caused by inefficient recovery during extraction. Cytokine concentrations from finger-prick samples were also found to be much more variable that those in venous blood samples.
Our results highlight the need to understand the stability of analytes of interest before committing to longitudinal collection and storage of samples in VAMS devices. These data give confidence that storage at 4 °C or colder was beneficial for cytokine stability. Wherein 25/31 cytokines were quantifiably stable at −20 °C when stored for 3 months and 17/21 were quantifiably stable after 5 months when stored at 4 °C.
Left ventricular (LV) diastolic dysfunction is highly prevalent in cats and is a functional hallmark of feline cardiomyopathy. The majority of cats with hypertrophic, restrictive, and dilated ...cardiomyopathy have echocardiographic evidence of abnormal LV filling, even during the occult (preclinical) phase. Moderate and severe diastolic dysfunction is an indicator of advanced myocardial disease, is associated with clinical signs including exercise intolerance and congestive heart failure, affects outcome, and influences therapeutic decisions. Therefore, identification and quantification of LV diastolic dysfunction are clinically important. Surrogate measures of diastolic function determined by transthoracic two-dimensional, M-mode, and Doppler echocardiographic (DE) methods have been used widely for such purpose. Major functional characteristics of LV diastole, including global function, relaxation and untwist, chamber compliance, filling volume, and the resultant filling pressures can be semi-quantified by echocardiographic methods, and variables retrieved from transmitral flow, pulmonary vein flow, and tissue Doppler recordings are most frequently used. Although there is still a critical lack of well-designed studies in the field, knowledge has steadily accumulated over the past 20 years, reference ranges of diastolic echocardiographic variables have been determined, epidemiological studies have been conducted, and new treatments of diastolic dysfunction in cats have been evaluated. This report will give the reader a summary of the current status in the field of feline diastology with focus on the noninvasive diagnostic methods and interpretation of echocardiographic surrogate measures of LV diastolic function. Lastly, a grading system using a composite of left atrial size and various DE variables potentially useful in the functional classification of LV diastole in cats is introduced.
Home rehabilitation requests subject to review by health authorities, restricted to patients with significant new-disability and limited caregiver support. (Provision of healthcare is regulated and ...reimbursed regionally.) Tanzania Local only Containment and mitigation: public gatherings ban, 30-day closure of schools, universities, training institutions, health screening at points of entry, 14-day quarantine for travellers from high-risk countries. Local KCMC. Example: care for older adults suspended unless an emergency, outpatient block appointments, reduced elective surgeries and prioritised emergency surgeries. Shift in rehabilitation hospital beds to maximise inpatient capacity; shift in rehabilitation personnel to provide greater acute hospital and community service support. CDC, Centers for Disease Control and Prevention; KCMC, Kilimanjaro Christian Medical Center.
EndoPredict (EP) is an RNA-based multigene test that predicts the likelihood of distant recurrence in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative ...(HER2-) breast cancer (BC) who are being treated with adjuvant endocrine therapy. Herein we report the prospective-retrospective clinical validation of EP in the node-positive, chemotherapy-treated, ER+/HER2- BC patients in the GEICAM 9906 trial.
The patients (N = 1,246) were treated either with six cycles of fluorouracil, epirubicin and cyclophosphamide (FEC) or with four cycles of FEC followed by eight weekly courses of paclitaxel (FEC-P), as well as with endocrine therapy if they had hormone receptor-positive disease. The patients were assigned to EP risk categories (low or high) according to prespecified cutoff levels. The primary endpoint in the clinical validation of EP was distant metastasis-free survival (MFS). Metastasis rates were estimated using the Kaplan-Meier method, and multivariate analysis was performed using Cox regression.
The molecular EP score and the combined molecular and clinical EPclin score were successfully determined in 555 ER+/HER2- tumors from the 800 available samples in the GEICAM 9906 trial. On the basis of the EP, 25% of patients (n = 141) were classified as low risk. MFS was 93% in the low-risk group and 70% in the high-risk group (absolute risk reduction = 23%, hazard ratio (HR) = 4.8, 95% confidence interval (CI) = 2.5 to 9.5; P < 0.0001). Multivariate analysis showed that, in this ER+/HER2- cohort, EP results are an independent prognostic parameter after adjustment for age, grade, lymph node status, tumor size, treatment arm, ER and progesterone receptor (PR) status and proliferation index (Ki67). Using the predefined EPclin score, 13% of patients (n = 74) were assigned to the low-risk group, who had excellent outcomes and no distant recurrence events (absolute risk reduction vs high-risk group = 28%; P < 0.0001). Furthermore, EP was prognostic in premenopausal patients (HR = 6.7, 95% CI = 2.4 to 18.3; P = 0.0002) and postmenopausal patients (HR = 3.3, 95% CI = 1.3 to 8.5; P = 0.0109). There were no statistically significant differences in MFS between treatment arms (FEC vs FEC-P) in either the high- or low-risk groups. The interaction test results between the chemotherapy arm and the EP score were not significant.
EP is an independent prognostic parameter in node-positive, ER+/HER2- BC patients treated with adjuvant chemotherapy followed by hormone therapy. EP did not predict a greater efficacy of FEC-P compared to FEC alone.
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