Triple-Negative Breast Cancer: An Update on Neoadjuvant Clinical Trials

Triple-negative breast cancer (TNBC) is an aggressive malignancy with a poor prognosis despite the high rates of response to chemotherapy. This scenario highlights the need to develop novel therapies and/or treatment strategies to reduce the mortality associated with TNBC. The neoadjuvant setting provides a model for rapid assessment of treatment efficacy with smaller patient accruals and over shorter periods of time compared to the traditional adjuvant setting. In addition, a clear surrogate endpoint of improved survival, known as pathologic complete response, already exists in this setting. Here, we review current data from completed and ongoing neoadjuvant clinical trials for TNBC

Focal Ca2+ Transient Detection in Smooth Muscle

Ca2+ imaging of smooth muscle provides insight into cellular mechanisms that may not result in changes of membrane potential, such as the release of Ca2+ from internal stores, and allows multiple cells to be monitored simultaneously to assess, for example, coupling in syncytial tissue. Subcellular Ca2+ transients are common in smooth muscle, yet are difficult to measure accurately because of the problems caused by their stochastic occurrence, over an often wide field of view, in an organ that it prone to contract. To overcome this problem, we've developed a series of imaging protocols and analysis routines to acquire and then analyse, in an automated fashion, the frequency, location and amplitude of such events. While this approach may be applied in other contexts, our own work involves the detection of local purinergic Ca2+ transients for locating transmitter release with submicron resolution

Late Quaternary slip rate on the Kern Canyon fault at Soda Spring, Tulare County, California

The Kern Canyon fault represents a major tectonic and physiographic boundary in the southern Sierra Nevada of east-central California. Previous investigations of the Kern Canyon fault underscore its importance as a Late Cretaceous and Neogene shear zone in the tectonic development of the southern Sierra Nevada. Study of the late Quaternary history of activity, however, has been confounded by the remote nature of the Kern Canyon fault and deep along-strike exhumation within the northern Kern River drainage, driven by focused fluvial and glacial erosion. Recent acquisition of airborne lidar (light detection and ranging) topography along the ∼140 km length of the Kern Canyon fault provides a comprehensive view of the active surface trace. High-resolution, lidar-derived digital elevation models (DEMs) for the northern Kern Canyon fault enable identification of previously unrecognized offsets of late Quaternary moraines near Soda Spring (36.345°N, 118.408°W). Predominately north-striking fault scarps developed on the Soda Spring moraines display west-side-up displacement and lack a significant sense of strike-slip separation, consistent with detailed mapping and trenching along the entire Kern Canyon fault. Scarp-normal topographic profiling derived from the lidar DEMs suggests normal displacement of at least 2.8 +0.6/–0.5 m of the Tioga terminal moraine crest. Cosmogenic 10Be exposure dating of Tioga moraine boulders yields a tight age cluster centered around 18.1 ± 0.5 ka (n = 6), indicating a minimum normal-sense fault slip rate of ∼0.1–0.2 mm/yr over this period. Taken together, these results provide the first clear documentation of late Quaternary activity on the Kern Canyon fault and highlight its role in accommodating internal deformation of the southern Sierra Nevada

Clinical features and survival among children with retinoblastoma in Uganda

AIMS: To characterise the clinical features, treatment and outcome of children diagnosed with retinoblastoma in Uganda. METHODS: The study comprised a 6-year nationwide enrolment with follow-up. RESULTS: In total, 282 cases were enrolled, 26% (72) were bilateral; 6% were lost to follow-up. Almost all diagnoses in the first affected eye were International Classification of Retinoblastoma group E or worse. Histology was available for 92%; of those, 45%, had extraocular tumour at diagnosis. Enucleation of the first eye was done for 271; 94 received radiotherapy to the socket and in the last 2 years, 70 children received chemotherapy. At close of study, 139 children had died. Survival, as determined in a proportional hazards model adjusted for age, sex, laterality and treatment era (pre or post introduction of chemotherapy), varied by extent of the tumour (p<0.001); children with only intraocular involvement were 80% less likely to die (HR=0.21, 95% CI 0.12 to 0.35) compared with children with extraocular involvement. CONCLUSIONS: Diagnostic delay results in relatively high mortality among children with retinoblastoma in Uganda. There is an urgent need for more effective treatment modalities, particularly chemotherapy, and nationwide efforts to encourage earlier access to medical care

Clinical features and survival among children with retinoblastoma in Uganda

AIMS: To characterise the clinical features, treatment and outcome of children diagnosed with retinoblastoma in Uganda. METHODS: The study comprised a 6-year nationwide enrolment with follow-up. RESULTS: In total, 282 cases were enrolled, 26% (72) were bilateral; 6% were lost to follow-up. Almost all diagnoses in the first affected eye were International Classification of Retinoblastoma group E or worse. Histology was available for 92%; of those, 45%, had extraocular tumour at diagnosis. Enucleation of the first eye was done for 271; 94 received radiotherapy to the socket and in the last 2 years, 70 children received chemotherapy. At close of study, 139 children had died. Survival, as determined in a proportional hazards model adjusted for age, sex, laterality and treatment era (pre or post introduction of chemotherapy), varied by extent of the tumour (p<0.001); children with only intraocular involvement were 80% less likely to die (HR=0.21, 95% CI 0.12 to 0.35) compared with children with extraocular involvement. CONCLUSIONS: Diagnostic delay results in relatively high mortality among children with retinoblastoma in Uganda. There is an urgent need for more effective treatment modalities, particularly chemotherapy, and nationwide efforts to encourage earlier access to medical care

Improving survival of retinoblastoma in Uganda

BACKGROUND: Diagnostic delay results in relatively high mortality among children with retinoblastoma in Uganda, where treatment was limited to surgery and, for some, radiotherapy. In order to improve outcomes, a simple programme of neoadjuvant and adjuvant chemotherapy was introduced. Here we report survival before and after this change to medical practice. METHODS: Affordable standard off-patent chemotherapy agents were administered by trained paramedical staff to groups of patients at the same time. Survival before and after the introduction of chemotherapy was monitored. Between 2006 and 2013 a total of 270 patients with retinoblastoma were included, 181 treated prior to chemotherapy and 89 after (beginning in 2009). We had 94% follow-up and 249 had histological verification of diagnosis. RESULTS: Using a proportional hazards model adjusted for age, sex and laterality, children treated after chemotherapy was introduced had a 37% lower risk of dying (HR 0.63, 95% CI 0.41 to 0.99) compared with children treated before. Prior to the introduction of chemotherapy only 15% of children who survived bilateral disease retained vision after treatment compared with 71% after chemotherapy. CONCLUSIONS: The introduction of chemotherapy proved safe and cost-effective in non-specialist hands and was associated with significant improvements in survival and, among bilateral cases, in preserving vision

New and improved proteomics technologies for understanding complex biological systems: Addressing a grand challenge in the life sciences

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93688/1/pmic7183.pd

Systematic Bias in Genomic Classification Due to Contaminating Non-neoplastic Tissue in Breast Tumor Samples

Abstract Background Genomic tests are available to predict breast cancer recurrence and to guide clinical decision making. These predictors provide recurrence risk scores along with a measure of uncertainty, usually a confidence interval. The confidence interval conveys random error and not systematic bias. Standard tumor sampling methods make this problematic, as it is common to have a substantial proportion (typically 30-50%) of a tumor sample comprised of histologically benign tissue. This "normal" tissue could represent a source of non-random error or systematic bias in genomic classification. Methods To assess the performance characteristics of genomic classification to systematic error from normal contamination, we collected 55 tumor samples and paired tumor-adjacent normal tissue. Using genomic signatures from the tumor and paired normal, we evaluated how increasing normal contamination altered recurrence risk scores for various genomic predictors. Results Simulations of normal tissue contamination caused misclassification of tumors in all predictors evaluated, but different breast cancer predictors showed different types of vulnerability to normal tissue bias. While two predictors had unpredictable direction of bias (either higher or lower risk of relapse resulted from normal contamination), one signature showed predictable direction of normal tissue effects. Due to this predictable direction of effect, this signature (the PAM50) was adjusted for normal tissue contamination and these corrections improved sensitivity and negative predictive value. For all three assays quality control standards and/or appropriate bias adjustment strategies can be used to improve assay reliability. Conclusions Normal tissue sampled concurrently with tumor is an important source of bias in breast genomic predictors. All genomic predictors show some sensitivity to normal tissue contamination and ideal strategies for mitigating this bias vary depending upon the particular genes and computational methods used in the predictor