Perspectives on shorter durations of anti-HER2 therapy in early-stage HER2-positive breast cancer: a patient survey.

PURPOSE: Despite previous studies proposing shorter durations of anti-HER2 therapy for selected patients with HER2-positive early breast cancer (EBC), 12-months remains standard of care. A survey was performed to assess patient perspectives and willingness to participate in studies evaluating shorter durations of anti-HER2 therapy. METHODS: Patients with HER2-positive EBC completing or having previously completed anti-HER2 therapy, were recruited by healthcare professionals at The Ottawa Hospital Cancer Centre to participate in an anonymous online survey. The primary objective was to learn about patients' perspectives on shorter durations (less than 12-months) of anti-HER2 therapy. Secondary objectives were to explore patients' interest in clinical trials of shorter durations of anti-HER2 therapy and the degree of increased breast cancer risk they would accept with a shorter treatment duration. RESULTS: Responses were received from 94 eligible patients. Most patients received Trastuzumab alone (78%, 73/94), while 13% (12/94) received trastuzumab and pertuzumab. Side effects were experienced by 52% (46/89), the most common being; fatigue (61%, 28/46), myalgia (37%, 17/46), and diarrhea (24%, 11/46). Most patients (88%, 78/89) did not find treatment bothersome. Regarding perspectives on shorter durations of anti-HER2 therapy, most (79%, 74/94) respondents stated they would agree to less treatment if it were possible to receive fewer treatments with the same cancer benefits. 56% of patients were interested in clinical trials, however, about half stated they would not be accepting of any increase in breast cancer recurrence risk. CONCLUSION: Trials to investigate who can safely and effectively be treated with shorter durations of anti-HER2 therapy are needed. This study provides important insights to patients' perspectives on shorter durations of anti-HER2 treatment, and their concerns regarding potential increased cancer risk with less treatment.

Slower response to treatment of iron-deficiency anaemia in pregnant women infected with HIV: a prospective cohort study.

OBJECTIVE: Antenatal anaemia is associated with increased peripartum transfusion requirement in South Africa. We studied whether HIV was associated with the response to treatment of iron-deficiency anaemia. DESIGN: Prospective cohort study. SETTING: Hospital-based antenatal anaemia clinic in South Africa. SAMPLE: Equal-sized cohorts of pregnant women testing positive for HIV (HIV+) and testing negative for HIV (HIV-) with iron-deficiency anaemia. METHODS: Haemoglobin trajectories of women with confirmed iron-deficiency anaemia (ferritin < 50 ng/ml) were estimated from the initiation of iron supplementation using mixed-effects modelling, adjusted for baseline HIV status, ferritin level, maternal and gestational ages and time-varying iron supplementation. MAIN OUTCOME MEASURES: Haemoglobin trajectories. RESULTS: Of 469 women enrolled, 51% were HIV+, 90% of whom were on antiretroviral therapy (with a mean CD4+ lymphocyte count of 403 cells/mm3 ). Anaemia diagnoses did not differ by HIV status. A total of 400 women with iron-deficiency anaemia were followed during treatment with oral or intravenous (6%) iron therapy. In multivariable analysis, haemoglobin recovery was 0.10 g/dl per week slower on average in women who were HIV+ versus women who were HIV- (P = 0.001), 0.01 g/dl per week slower in women with higher baseline ferritin (P < 0.001) and 0.06 g/dl per week faster in women who were compliant with oral iron therapy (P = 0.002). CONCLUSIONS: Compared with women who were HIV-, women who were HIV+ with iron-deficiency anaemia had slower but successful haemoglobin recovery with iron therapy. Earlier effective management of iron deficiency could reduce the incidence of peripartum blood transfusion. TWEETABLE ABSTRACT: Among pregnant women with iron-deficiency anaemia in South Africa, HIV slows haemoglobin recovery in response to oral iron therapy.

A randomized trial of individualized versus standard of care antiemetic therapy for breast cancer patients at high risk for chemotherapy-induced nausea and vomiting.

PURPOSE: Despite triple antiemetic therapy use for breast cancer patients receiving emetogenic chemotherapy, nausea remains a clinical challenge. We evaluated adding olanzapine (5 mg) to triple therapy on nausea control in patients at high personal risk of chemotherapy-induced nausea and vomiting (CINV). METHODS: This multi-centre, placebo-controlled, double-blind trial randomized breast cancer patients scheduled to receive neo/adjuvant chemotherapy with anthracycline-cyclophosphamide or platinum-based chemotherapy to olanzapine (5 mg, days 1-4) or placebo. Primary endpoint was frequency of self-reported significant nausea, repeated for all cycles of chemotherapy. Secondary endpoints included: duration of nausea, overall total control of CINV, Health Related Quality of Life (HRQoL) using FLIE questionnaire, use of rescue mediation and treatment-related adverse events. RESULTS: 218 eligible patients were randomised to placebo (105) or olanzapine (113). From days 0-5 following each cycle of chemotherapy, 41.3% (95%CI: 36.1-46.7%) of patients in the placebo group reported significant nausea compared to 27.7% (95%CI: 23.2-32.4%) in the olanzapine group (p = 0.001). Across all cycles of chemotherapy, patients receiving olanzapine experienced a statistically significant improvement in HRQoL (p < 0.001). Grade 1/2 sedation was the most commonly side effect reported at 40.8% in the placebo group vs. 54.1% with olanzapine (p < 0.001). CONCLUSION: In patients at high personal risk of CINV, the addition of olanzapine 5 mg daily to standard antiemetic therapy significantly improves the control of nausea, HRQoL, with no unexpected toxicities.

A multicentre, randomised trial comparing schedules of G-CSF (filgrastim) administration for primary prophylaxis of chemotherapy-induced febrile neutropenia in early stage breast cancer.

BACKGROUND: The optimal duration of filgrastim as primary febrile neutropenia (FN) prophylaxis in early breast cancer patients is unknown, with 5, 7 or 10 days being commonly prescribed. This trial evaluates whether 5 days of filgrastim was non-inferior to 7/10 days. PATIENTS AND METHODS: In this randomised, open-label trial, early breast cancer patients who were to receive filgrastim as primary FN prophylaxis were randomly allocated to 5 versus 7 versus 10 days of filgrastim for all chemotherapy cycles. A protocol amendment in November 2017 allowed subsequent patients (N = 324) to be randomised to either 5 or 7/10 days. The primary outcome was a composite of either FN or treatment-related hospitalisations. Secondary outcomes included chemotherapy dose reductions, delays and discontinuations. Analyses were carried out by per protocol (primary) and intention-to-treat, and the non-inferiority margin was set at 3% for the risk of having FN and/or hospitalisation per cycle of chemotherapy. RESULTS: Patients (N = 466) were randomised to receive 5 (184, 39.5%), or 7/10 (282, 60.5%) days of filgrastim. In our primary analysis, the difference in risk of either FN or treatment-related hospitalisation per cycle was -1.52% [95% confidence interval (CI): -3.22% to 0.19%] suggesting non-inferiority of a 5-day filgrastim schedule compared with 7/10-days. The difference in events per cycle for FN was 0.11% (95% CI: -1.05 to 1.27) while for treatment-related hospitalisations it was -1.68% (95% CI: -2.73% to -0.63%). The overall proportions of patients having at least one occurrence of either FN or treatment-related hospitalisation were 11.8% and 14.96% for the 5- and 7/10-day groups, respectively (risk difference: -3.17%, 95% CI: -9.51% to 3.18%). CONCLUSION: Five days of filgrastim was non-inferior to 7/10 days. Given the cost and toxicity of this agent, 5 days should be considered standard of care. CLINICALTRIALS. GOV REGISTRATION: NCT02428114 and NCT02816164.

Angioleiomyoma of the inferior turbinate: a rare cause of isolated facial pain.

We present the case of a 33-year-old man with right-sided facial pain. Clinical examination revealed an isolated mass attached to the right inferior turbinate. This was confirmed with computed tomography. Excision was achieved endoscopically and histology revealed an angioleiomyoma. Full symptomatic relief was achieved after surgical excision. Less than 1% of angioleiomyoma lesions are found within the sinonasal cavity. We describe the first documented presentation of angioleiomyoma as a cause of isolated, unilateral facial pain; a very common presentation to the otorhinolaryngology clinic. We promote consideration of angioleiomyoma as a different diagnosis in the presence of facial pain and a unilateral sinonasal lesion. Endoscopic resection provides complete symptomatic resolution.

OCTANE (Ontario-wide Cancer Targeted Nucleic Acid Evaluation): a platform for intraprovincial, national, and international clinical data-sharing.

Cancer is a genetic disease resulting from germline or somatic genetic aberrations. Rapid progress in the field of genomics in recent years is allowing for increased characterization and understanding of the various forms of the disease. The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (octane) clinical trial, open at cancer centres across Ontario, aims to increase access to genomic sequencing of tumours and to facilitate the collection of clinical data related to enrolled patients and their clinical outcomes. The study is designed to assess the clinical utility of next-generation sequencing (ngs) in cancer patient care, including enhancement of treatment options available to patients. A core aim of the study is to encourage collaboration between cancer hospitals within Ontario while also increasing international collaboration in terms of sharing the newly generated data. The single-payer provincial health care system in Ontario provides a unique opportunity to develop a province-wide registry of ngs testing and a repository of genomically characterized, clinically annotated samples. It also provides an important opportunity to use province-wide real-world data to evaluate outcomes and the cost of ngs for patients with advanced cancer. The octane study is attempting to translate knowledge to help deliver precision oncology in a Canadian environment. In this article, we discuss the background to the study and its implementation, current status, and future directions.

Nasal obstruction secondary to an inverted midline supernumerary tooth.

We present the case of a 36-year-old man who presented with left-sided nasal obstruction and facial pain. Clinical examination and computed tomography revealed an inverted midline supernumerary tooth buckling and deviating the nasal septum to the left. Full surgical resection of the tooth was achieved through a minimally invasive endoscopic septoplasty with full resolution of symptoms. There is little precedent within the literature to guide our management in this case and therefore we offer a successful surgical treatment strategy.

Optimizing vascular access for patients receiving intravenous systemic therapy for early-stage breast cancer-a survey of oncology nurses and physicians.

Background: Despite advances in systemic therapy choices for patients with early-stage breast cancer, optimal practices for intravenous (IV) access remain unknown. That lack of knowledge holds particularly true for the use of central venous access devices (cvads) such as peripherally inserted central catheters (piccs) and implanted vascular access devices (ports). Methods: Using a survey of Canadian oncologists and oncology nurses responsible for the care of breast cancer patients, we evaluated current access practices, perceptions of complications, and perceptions of risk, and we estimated complication rates and evaluated perceived risk factors for lymphedema. Results: Survey responses were received from 25 physicians and 57 oncology nurses. Administration of trastuzumab or an anthracycline was associated with a higher likelihood of a cvad being recommended. Other factors associated with recommendation of a cvad included prior difficult IV access and a recommendation from the chemotherapy nurse. Although the complication rates perceived to be associated with the use of piccs and ports remained high, respondents felt that cvads might improve patient quality of life. Risk factors perceived to be associated with the risk of lymphedema were axillary lymph node dissection, radiation to the axilla, and line-associated infection. Factors known to be unrelated to lymphedema risk (specifically, blood draws and blood pressure measurement) continue to be perceived as posing a higher risk. Conclusions: Despite widespread use of chemotherapy for patients with breast cancer, the type of venous access used for treatment varies significantly, as do perceptions about the risks of cvad use and the risk for lymphedema development. Further prospective studies are needed to identify best-practice strategies.

Perceptions of vascular access for intravenous systemic therapy and risk factors for lymphedema in early-stage breast cancer-a patient survey.

Background: The choice of vascular access for systemic therapy administration in breast cancer remains an area of clinical equipoise, and patient preference is not consistently acknowledged. Using a patient survey, we evaluated the patient experience with vascular access during treatment for early-stage breast cancer and explored perceived risk factors for lymphedema. Methods: Patients who had received systemic therapy for early-stage breast cancer were surveyed at 2 Canadian cancer centres. Results: Responses were received from 187 patients (94%). The route of vascular access was peripheral intravenous line (IV) in 24%, a peripherally inserted central catheter (picc) in 42%, and a surgically inserted central catheter (port) in 34%. Anthracycline-based regimens were associated with a greater use of central vascular access devices (cvads- that is, a picc or port; 86/97, 89%). Trastuzumab use was associated with greater use of ports (49/64, 77%). Although few patients (7%) reported being involved in the decisions about vascular access, most were satisfied or very satisfied (88%) with their access type. Patient preference centred mainly on avoiding delays in the initiation of chemotherapy. Self-reported rates of complications (183 evaluable responses) were infiltration with peripheral IVs (9/44, 20%), local skin infections with piccs (7/77, 9%), and thrombosis with ports (4/62, 6%). Perceived risk factors for lymphedema included use of the surgical arm for blood draws (117/156, 75%) and blood pressure measurement (115/156, 74%). Conclusions: Most patients reported being satisfied with the vascular access used for their treatment. Improved education and understanding about the evidence-based requirements for vascular access are needed. Perceived risk factors for lymphedema remain variable and are not evidence-based.

Optimal sequence of adjuvant endocrine and radiation therapy in early-stage breast cancer - A systematic review.

IMPORTANCE: Clinical equipoise exists around the optimal time to start adjuvant endocrine therapy in patients who will receive post-operative radiotherapy for breast cancer. Concerns continue to exist regarding potential reduced efficacy, or increased toxicity, when radiation, and endocrine therapy are administered concurrently. OBJECTIVE: To perform a systematic review of studies comparing outcomes between sequential and concurrent adjuvant radiation and endocrine therapy in early-stage breast cancer. All modalities of radiation therapy were considered, and endocrine therapy could be either tamoxifen or an aromatase inhibitor. Outcomes of interest included; local, regional or distant recurrence, overall survival and treatment-related toxicities. EVIDENCE REVIEWED: PubMed, Ovid Medline, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from 1946 to December 2017. Two reviewers independently assessed each citation using the criteria outlined above. Study quality was assessed using the Cochrane Collaboration's tool for prospective studies, and the Newcastle-Ottawa scale for retrospective studies. FINDINGS: Of 2137 unique citations identified, 13 met eligibility criteria. Eleven were unique studies (7569 patients), while 2 of the studies were updated analyses of previous studies. Studies evaluated the timing of adjuvant radiation, and tamoxifen (5 studies, 1550 patients), or aromatase inhibitors (6 studies, 6019 patients). We identified 1 complete randomized clinical trial (150 patients), and 5 retrospective studies (1580 patients), in addition to conference abstracts (5 studies, 5839 patients). Overall, none of the studies showed a significant difference in efficacy, or toxicity, with concurrent versus sequential treatment. However, given the significant heterogeneity of the study populations, it was not possible to conduct a meta-analysis. CONCLUSIONS AND RELEVANCE: In the absence of high quality data, adequately powered randomized trials are required to answer this important clinical question.

Taxane acute pain syndrome (TAPS) in patients receiving chemotherapy for breast or prostate cancer: a prospective multi-center study.

BACKGROUND: Taxane acute pain syndrome (TAPS) is characterized by myalgias and arthralgias starting 2-3 days after taxane-based chemotherapy and lasting up to 7 days. In the absence of validated tools, many studies use the presence of both the myalgia and arthralgia components of the Common Terminology Criteria for Adverse Events (CTCAE) to define TAPS. The present study prospectively evaluated the frequency, severity, and impact of TAPS in patients with breast or prostate cancer. PATIENTS AND METHODS: In this prospective, non-randomized study, patients with breast or prostate cancer commencing taxane-based chemotherapy completed the CTCAE (version 4.03), the Functional Assessment of Cancer Therapy-Taxane (FACT-T), and Brief Pain Inventory (BPI) questionnaires at baseline and once between days 5 and 7 of each chemotherapy cycle. RESULTS: From March 2015 to April 1, 2016, 75 patients (breast n = 66, prostate n = 9) were enrolled; 83% received docetaxel and 16% paclitaxel and 1% withdrew. After the first cycle of taxane, TAPS was reported by 25/69 (36.2%) patients; a further 8/69 (18.2%) reporting TAPS after a subsequent chemotherapy treatment. Overall incidence of TAPS was 33/75 (44%). While associated with detrimental scores on FACT-T and BPI as well as increased use of analgesics in 63% (21/33) of patients with TAPS, TAPS did not lead to alterations in chemotherapy dosing. CONCLUSIONS: TAPS is common after taxane-based chemotherapy, and its presence is associated with reduced quality of life and increased analgesic requirements. Prospective patient-reported outcome assessments are crucial to help individualize treatment strategies and improve management of TAPS.

Effects on bone resorption markers of continuing pamidronate or switching to zoledronic acid in patients with high risk bone metastases from breast cancer.

BACKGROUND: Switching patients who remain at high risk of skeletal related events (SREs) despite pamidronate to the more potent bisphosphonate zoledronate, may be an effective treatment strategy. As part of a previously reported clinic study in this setting, we evaluated whether biomarkers for bone resorption, such as Bone-Specific Alkaline Phosphatase (BSAP), bone sialoprotein (BSP), and N-terminal telopeptide (NTX) correlated with subsequent SRE risk. METHODS: Breast cancer patients who remained at high risk of SREs despite at least 3 months of q.3-4 weekly pamidronate were randomized to either continue on pamidronate or to switch to zoledronate (4 mg) once every 4 weeks for 12-weeks. High risk bone metastases were defined by either: occurrence of a prior SRE, bone pain, radiologic progression of bone metastases and/or serum C-terminal telopeptide (CTx) levels > 400 ng/L despite pamidronate use. Serum samples were collected at baseline and weeks 1, 4, 8 and 12 (CTx and BSAP) and baseline and week 12 (NTx and BSP), and all putative biomarkers were measured by ELISA. Follow up was extended to 2 years post trial entry for risk of subsequent SREs. The Kaplan-Meier method was used to estimate time-to-event outcomes. Generalized estimating equations (GEE) were used to evaluate if laboratory values over time or the change in laboratory values from baseline were associated with having a SRE within the time frame of this study. RESULTS: From March 2012 to May 2014, 76 patients were screened, with 73 eligible for enrolment. All 73 patients were available for biochemical analysis, with 35 patients receiving pamidronate and 38 patients receiving zoledronate. The GEE analysis found that no laboratory value was associated with having a subsequent SRE. Interaction between visit and laboratory values was also investigated, but no interaction effect was statistically significant. Only increased number of lines of prior hormonal treatment was associated with subsequent SRE risk. CONCLUSION: Our analysis failed to find any association between serum BSAP, BSP, CTx or NTx levels and subsequent SRE risk in this cohort of patients. This lack of correlation between serum biomarkers and clinical outcomes could be due to influences of prior bisphosphonate treatment or presence of extra-osseous metastases in a significant proportion of enrolled patients. As such, caution should be used in biomarker interpretation and use to direct decision making regarding SRE risk for high risk patients in this setting.

Effects of depot-medroxyprogesterone acetate on the immune microenvironment of the human cervix and endometrium: implications for HIV susceptibility.

Depot-medroxyprogesterone acetate is a commonly used injectable contraceptive that has been associated with an increased risk of HIV acquisition. This study compares effects of depot-medroxyprogesterone acetate on immune parameters from several upper reproductive tract compartments relevant to HIV-1 susceptibility in repetitive samples from 15 depot-medroxyprogesterone acetate users and 27 women not on hormonal contraceptives. Compared with samples from unexposed women in the mid-luteal phase, depot-medroxyprogesterone acetate use was associated with: increased endocervical concentrations of MCP1 and IFNalpha2; decreased endocervical concentrations of IL1beta and IL6; increased proportions of endometrial CD4+ and CD8+ cells expressing the activation marker HLADR; increased density of endometrial macrophages; and decreased density of endometrial regulatory T cells. Unlike previous reports with samples from the vagina, we did not observe increased expression of the HIV co-receptor CCR5 on CD4+ T cells in the endocervix or endometrium. Our results indicate important differences in anatomic compartments regarding mechanisms by which depot-medroxyprogesterone acetate could be associated with increased risk of HIV acquisition, including increased recruitment of macrophages to the endometrium, decreased levels of pro-inflammatory cytokines in the endocervix possibly leading to enhanced susceptibility to viral infection, and activation of endometrial T cells.

Hughes Abdominal Repair Trial (HART) - Abdominal wall closure techniques to reduce the incidence of incisional hernias: study protocol for a randomised controlled trial.

BACKGROUND: Incisional hernias are common complications of midline closure following abdominal surgery and cause significant morbidity, impaired quality of life and increased health care costs. The 'Hughes Repair' combines a standard mass closure with a series of horizontal and two vertical mattress sutures within a single suture. This theoretically distributes the load along the incision length as well as across it. There is evidence to suggest that this technique is as effective as mesh repair for the operative management of incisional hernias; however, no trials have compared the Hughes Repair with standard mass closure for the prevention of incisional hernia formation following a midline incision. METHODS/DESIGN: This is a 1:1 randomised controlled trial comparing two suture techniques for the closure of the midline abdominal wound following surgery for colorectal cancer. Full ethical approval has been gained (Wales REC 3, MREC 12/WA/0374). Eight hundred patients will be randomised from approximately 20 general surgical units within the United Kingdom. Patients undergoing open or laparoscopic (more than a 5-cm midline incision) surgery for colorectal cancer, elective or emergency, are eligible. Patients under the age of 18 years, those having mesh inserted or undergoing musculofascial flap closure of the perineal defect in abdominoperineal wound closure, and those unable to give informed consent will be excluded. Patients will be randomised intraoperatively to either the Hughes Repair or standard mass closure. The primary outcome measure is the incidence of incisional hernias at 1 year as assessed by standardised clinical examination. The secondary outcomes include quality of life patient-reported outcome measures, cost-utility analysis, incidence of complete abdominal wound dehiscence and C-POSSUM scores. The incidence of incisional hernia at 1 year, assessed by computerised tomography, will form a tertiary outcome. DISCUSSION: A feasibility phase has been completed. The results of the study will be used to inform current and future practice and potentially reduce the risk of incisional hernia formation following midline incisions. TRIAL REGISTRATION NUMBER: ISRCTN 25616490 . Registered on 1 January 2012.

Estrogen, progesterone, and HER2/neu receptor discordance between primary and metastatic breast tumours-a review.

Discordance in estrogen (ER), progesterone (PR), and HER2/neu status between primary breast tumours and metastatic disease is well recognized. In this review, we highlight how receptor discordance between primary tumours and paired metastasis can help elucidate the mechanism of metastasis but can also effect patient management and the design of future trials. Discordance rates and ranges were available from 47 studies (3384 matched primary and metastatic pairs) reporting ER, PR, and HER2/neu expression for both primary and metastatic sites. Median discordance rates for ER, PR, and HER2/neu were 14 % (range 0-67 %, IQR 9-25 %), 21 % (range 0-62 %, IQR 15-41 %), and 10 % (range 0-44 %, IQR 4-17 %), respectively. Loss of receptor expression was more common (9.17 %) than gain (4.51 %). Discordance rates varied amongst site of metastasis with ER discordance being highest in bone metastases suggesting that discordance is a true biological phenomenon. Discordance rates vary for both the biomarker and the metastatic site. Loss of expression is more common than gain. This can affect patient management as it can lead to a reduction in both the efficacy and availability of potential therapeutic agents. Future studies are recommended to explore both the mechanisms of discordance as well as its impact on patient outcome and management.

Should de-escalation of bone-targeting agents be standard of care for patients with bone metastases from breast cancer? A systematic review and meta-analysis.

BACKGROUND: De-escalation of bone-targeted agents, such as bisphosphonates and denosumab, from 4- to 12-weekly dosing is an increasingly used strategy in patients with bone metastases from breast cancer. It is unclear whether there is sufficient evidence to support de-escalation as a standard of care. METHODS: A systematic review of randomized trials comparing standard 4-weekly administration of bone-targeted agents with de-escalated (Q12-weekly) dosing in breast cancer patients was carried out. Medline, PubMed and the Cochrane Register of Controlled Trials were searched from inception until November 2014 for relevant studies. Outcomes of interest included skeletal-related event (SRE) rates, bone pain, adverse events (AEs) and bone turnover biomarkers. Random-effects meta-analyses were carried out. RESULTS: A total of nine citations representing seven unique studies were eligible. One study is ongoing with no reported data. Six studies reported data for at least one outcome of interest. Data were available comparing standard versus de-escalated therapy for pamidronate (1 study, 38 patients), zoledronate (3 studies, 1117 patients) and denosumab (2 studies, 284 patients). Meta-analysis of five trials reporting data for on-study SRE rates between standard (61/443 patients) and de-escalated (49/392 patients) arms produced a summary risk ratio of 0.90 (95% confidence interval 0.63-1.29). Meta-analyses of data for AEs and bone turnover biomarkers also showed no statistically significant differences between standard and de-escalated arms, though only limited numbers of patients and events were present for most analyses. CONCLUSION: In this systematic review of studies of bisphosphonates and denosumab, there appears to be no difference in SREs or pain with de-escalated therapy. While a large, hopefully definitive study is ongoing, the data presented so far are consistent with de-escalation of bone-targeting agents becoming a standard of care for patients with bone metastases from breast cancer.

The pathophysiology, diagnosis and treatment of the acute coagulopathy of trauma and shock: a literature review.

BACKGROUND: The acute coagulopathy of trauma and shock is associated with significant mortality and, currently, there are no validated laboratory tests which allow for a rapid recognition and treatment of this condition. Therefore, early detection of any clot abnormality in trauma could improve the diagnosis of trauma-associated coagulopathy and subsequent interventions. METHODS: Review of the literature. RESULTS: The standard laboratory tests, including prothrombin time and activated partial thromboplastin time, are unreliable and describe only an isolated fragment of the complex coagulation pathways. Additionally, thromboelastography and thromboelastometry operate in a non-linear regime which implies that clot formation is the product of both the clotting process and the effect of the measurement. The assessment of the clot microstructure using a scanning electron microscope has resulted in a subjective analysis of a clot structure, showing also poor correlation between the coagulation pathways and clot development. The fractal dimension provides information on the structure and quality of the initial clot, which subsequently acts as a template for how the mature clot will behave. However, these data require further verification in an in vivo setting. At present, the treatment of the coagulopathy is delivered by empirically administered massive transfusion protocols, which lack a specific target for replacement therapy. CONCLUSIONS: There is enough evidence to demonstrate that we urgently need a robust test, which would determine and quantify both the rate and the extent of coagulation abnormalities. This could help to tailor the treatment of coagulopathy according to the patient's needs.

Neoadjuvant endocrine therapy and window of opportunity trials: new standards in the treatment of breast cancer?

Until recently, the use of neoadjuvant endocrine therapy was mainly restricted to those patients whose general frailty or comorbidities were contraindications to surgery. There is now increased evidence that certain patient populations (i.e. older patients with hormone-receptor positive disease) can gain as good a pathologic response, with considerably less toxicity, from neoadjuvant endocrine therapy than from neoadjuvant chemotherapy. Optimization of neoadjuvant endocrine therapy is therefore an important therapeutic goal. However, possibly of greater importance in the overall management of breast cancer, is the increased interest in exploring the effects of brief periods of endocrine therapy on in vivo biomarkers, in so called window of opportunity trials. These trials can not only be used to identify the mechanisms of action of novel agents but also to predict optimal subsequent adjuvant therapy for individual patients. While this paper will briefly review the history of neoadjuvant endocrine therapy, more emphasis will be on the evaluation of pivotal window of opportunity trials that will likely lead to a long awaited paradigm shift in the management of breast cancer.