Previous studies suggest elevated factor VIII is a common, independent risk factor for venous thromboembolism (VTE); however, these studies included secondary and idiopathic VTE. We sought to explore ...the association between elevated factor VIII and VTE in Canadian patients with idiopathic thrombosis, and confirm the current upper factor VIII reference range was appropriate. We enrolled 300 consecutive patients with idiopathic VTE who were matched to friend controls by age, sex and ethnicity. Factor VIII levels were measured and compared between cases and controls. The optimal cut-off value to designate factor VIII levels as elevated was determined using a variety of methods. The optimal upper cut-off value for factor VIII levels was 270 IU/dl. In the logistic regression analysis, cases were more likely to have elevated factor VIII levels (OR:8.76), as were females (OR:1.93) and older subjects (OR: 1.05). Factor VIII cutoffs for a 95% specificity by age were 238 IU/dl for subjects <40 years, 248 IU/dl age 40-55 years, 261 IU/dl age 56-70 years, and 313 IU/dl age >70. Our findings confirm that elevated factor VIII is associated with an increased risk of idiopathic VTE. In our patients and matched controls, the current upper limit of normal (150 IU/dl) for factor VIII is not of clinical use. We propose that the upper limit be increased to 270 IU/dl or individual labs should establish their upper limit if they wish their assays to be discriminatory in patients with VTE. Age specific cut-offs may be clinically relevant.
Abstract Purpose This is the first case report where 1.25 mg intravitreal bevacizumab (IVB) correlated with choroidal mass resolution from metastatic breast cancer given concurrently with ...chemotherapy demonstrating, at best, disease stability in other organs. Study design Case report. Methods Upon confirmation of choroidal, liver and bone metastasis from breast carcinoma, a 72-year-old female received four intravitreal bevacizumab 1.25 mg injections based on the presence of subretinal and intraretinal fluid. Visual outcomes were analyzed by ophthalmologic evaluation, B-scan, fluorescein angiography, and optical coherence tomography. Results After 3 treatments of 1.25 mg intravitreal bevacizumab, visual acuity improved from 20/125 OD to 20/30 OD. These results were maintained for 5 months, after which a 4th IVB injection was given to try to further improve visual outcomes. Following this, complete resolution of the mass was observed with remaining pigmentary changes and vision improved to 20/25 one month following this. IVB was administered concurrently to systemic chemotherapy that demonstrated at best disease stability in metastases in other organs. Conclusion In this case 1.25 mg intravitreal bevacizumab proved to be a safe, effective and relatively easy treatment for choroidal metastasis from breast cancer. An important benefit of intravitreal bevacizumab therapy for choroidal metastasis is the ease of administration and minimal time commitment required as compared to other therapies. Further studies should be conducted to confirm the appropriate dosing and long-term outcomes of intravitreal bevacizumab to treat choroidal metastasis.
Overexpression and amplification of the neu (c-erbB2, ERBB2) protooncogene have been implicated in the development of aggressive human breast cancer. To directly assess the effect of mammary ...gland-specific expression of the neu protooncogene, transgenic mice carrying unactivated neu under the transcriptional control of the mouse mammary tumor virus promoter/enhancer were established. By contrast to the rapid tumor progression observed in several transgenic strains carrying the activated neu transgene, expression of unactivated neu in the mammary epithelium resulted in the development of focal mammary tumors after long latency. The majority of the mammary tumors analyzed expressed elevated levels of neu-encoded mRNA and protein. Overexpression of neu in the mammary tumors was also associated with elevated neu intrinsic tyrosine kinase activity and the de novo tyrosine phosphorylation of several cellular proteins. Interestingly, many of the tumor-bearing transgenic mice developed secondary metastatic tumors in the lung. These observations suggest that overexpression of the unactivated neu protein can induce metastatic disease after long latency.
Currently, antiangiogenic strategies in metastatic breast cancer have demonstrated modest improvements in progression-free survival (PFS) but not improved quality or duration of survival, warranting ...evaluation of new agents in a placebo-controlled setting. Ramucirumab is a human immunoglobulin G1 antibody that binds vascular endothelial growth factor receptor-2 and blocks ligand-stimulated activation. The ROSE/TRIO-012 trial evaluated ramucirumab with docetaxel in unresectable, locally recurrent, or metastatic breast cancer.
In this double-blind, placebo-controlled, randomized, multinational phase III trial, 1,144 patients with human epidermal growth factor receptor 2 (HER2) -negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting were randomly assigned at a two-to-one ratio to receive docetaxel 75 mg/m(2) plus ramucirumab 10 mg/kg or docetaxel 75 mg/m(2) plus placebo once every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographic region. An independent data monitoring committee oversaw the trial. The primary end point was investigator-assessed PFS.
Median PFS in patients treated with ramucirumab plus docetaxel was 9.5 months, compared with 8.2 months in patients who received placebo plus docetaxel (hazard ratio HR, 0.88; P = .077). Median overall survival was 27.3 months in patients who received ramucirumab plus docetaxel, compared with 27.2 months in patients who received placebo plus docetaxel (HR, 1.01; P = .915). Toxicities seen at significantly higher rates in patients receiving ramucirumab included fatigue, hypertension, febrile neutropenia, palmar-plantar erythrodysesthesia syndrome, and stomatitis.
Addition of ramucirumab to docetaxel in HER2-negative advanced breast cancer did not meaningfully improve important clinical outcomes.
Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent ...chemoradiotherapy for locally advanced HNSCC.
In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m2) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03040999, and is active but not recruiting.
Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1–52·3). Median event-free survival was not reached (95% CI 44·7 months–not reached) in the pembrolizumab group and 46·6 months (27·5–not reached) in the placebo group (hazard ratio 0·83 95% CI 0·68–1·03; log-rank p=0·043 significance threshold, p≤0·024). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 27% of 398 participants in the pembrolizumab group vs 100 25% of 398 participants in the placebo group), stomatitis (80 20% vs 69 17%), anaemia (80 20% vs 61 15%), dysphagia (76 19% vs 62 16%), and decreased lymphocyte count (76 19% vs 81 20%). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 11% vs 25 6%), acute kidney injury (33 8% vs 30 8%), and febrile neutropenia (24 6% vs seven 2%). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis).
Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches.
Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.
Lymphedema is a prevalent long-term effect of breast cancer treatment that is associated with reduced quality of life. More recent observational data suggest that the addition of night-time ...compression to day-time use of a compression garment results in better long-term control of arm lymphedema. The primary objectives of the randomized controlled phase of the trial are to determine the efficacy of night-time compression on arm lymphedema volume maintenance and quality of life in breast cancer survivors who have completed intensive reduction treatment for their lymphedema.
The study will be a parallel 3-arm, multi-centre randomized fast-track trial. A total of 120 women with breast cancer related lymphedema will be recruited from 3 centres in Canada and randomized to group 1: Day-time compression garment alone or Group 2: Day-time compression garment + night-time compression bandaging or Group 3: Day-time compression garment + use of a night-time compression system garment. The duration of the primary intervention period will be 12 weeks. The follow-up period after the intervention (weeks 13 to 24) will follow a longitudinal observational design. The primary outcome variables: differences from baseline to week 12 in arm volume and quality of life (Lymphoedema Functioning, Disability and Health Questionnaire: Lymph-ICF). Secondary outcomes include bioimpedance analysis, sleep disturbance and self-efficacy. All measurements are standardized and will be performed prior to randomization, and at weeks 6, 12, 18 and 24.
The use of night-time compression as a self-management strategy for chronic breast cancer related lymphedema is seen as an innovative approach to improve long-term control over the condition. This trial aims to advance the knowledge on self-management strategies for lymphedema.
This trial was registered at clinicaltrials.gov on July 9(th), 2014 ( NCT02187289 ).
Breast cancers are routinely assessed for estrogen receptor status using immunohistochemical assays to assist in patient prognosis and clinical management. Specific assays vary between laboratories, ...and several antibodies have been validated and recommended for clinical use. As numerous factors can influence assay performance, many laboratories have opted for ready-to-use assays using automated stainers to improve reproducibility and consistency. Three commonly used autostainer vendors—Dako, Leica, and Ventana—all offer such estrogen receptor assays; however, they have never been directly compared. Here, we present a systematic comparison of three platform-specific estrogen receptor ready-to-use assays using a retrospective, tamoxifen-treated, breast cancer cohort from patients who were treated in Calgary, Alberta, Canada from 1985 to 2000. We found all assays showed good intra-observer agreement. Inter-observer pathological scoring showed some variability: Ventana had the strongest agreement followed closely by Dako, whereas Leica only showed substantial agreement. We also analyzed each estrogen receptor assay with respect to 5-year disease-free survival, and found that all performed similarly in univariate and multivariate models. Determination of measures of test performance found that the Leica assay had a lower negative predictive value than Dako or Ventana, compared with the original ligand-binding assay, while other measures—sensitivity, specificity, positive predictive value, and accuracy—were comparable between the three ready-to-use assays. When comparing against disease-free survival, the difference in negative predictive value between the vendor assays were not as extreme, but Dako and Ventana still performed slightly better than Leica. Despite some discordance, we found that all ready-to-use assays were comparable with or superior to the ligand-binding assay, endorsing their continued use. Our analysis also allowed for exploration of estrogen receptor-negative, progesterone receptor-positive cases, and we discovered that this phenotype was not consistent across the assays, suggesting this might be an artifact.
Activation of the c-Src tyrosine kinase has been implicated as an important step in the induction of mammary tumors in both mice and humans. To directly assess the effect of mammary gland-specific ...expression of activated c-Src, we established transgenic mice that carry a constitutively activated form of c-src under transcriptional control of the murine mammary tumor virus long terminal repeat. Female mice derived from several independent transgenic lines lactate poorly as a consequence of an impairment in normal mammary epithelial development. In addition to this lactation defect, female mice frequently develop mammary epithelial hyperplasias, which occasionally progress to frank neoplasias. Taken together, these observations suggest that expression of activated c-Src in the mammary epithelium of transgenic mice is not sufficient for induction of mammary tumors.
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