Existing approaches to ‘algorithmic accountability’, such as transparency, provide an important baseline, but are insufficient to address the (potential) harm to human rights caused by the use of ...algorithms in decision-making. In order to effectively address the impact on human rights, we argue that a framework that sets out a shared understanding and means of assessing harm; is capable of dealing with multiple actors and different forms of responsibility; and applies across the full algorithmic life cycle, from conception to deployment, is needed. While generally overlooked in debates on algorithmic accountability, in this article, we suggest that international human rights law already provides this framework. We apply this framework to illustrate the effect it has on the choices to employ algorithms in decision-making in the first place and the safeguards required. While our analysis indicates that in some circumstances, the use of algorithms may be restricted, we argue that these findings are not ‘anti-innovation’ but rather appropriate checks and balances to ensure that algorithms contribute to society, while safeguarding against risks.
Background
In the Trastuzumab for GAstric cancer (ToGA) study, trastuzumab plus chemotherapy improved median overall survival by 2.7 months in patients with human epidermal growth factor receptor 2 ...(HER2)-positive immunohistochemistry (IHC) 3+/fluorescence in situ hybridization-positive gastric/gastroesophageal junction cancer compared with chemotherapy alone (hazard ratio 0.74). Post hoc exploratory analyses in patients expressing higher HER2 levels (IHC 2+/fluorescence in situ hybridization-positive or IHC 3+) demonstrated a 4.2-month improvement in median overall survival with trastuzumab (hazard ratio 0.65). The ToGA study provides the largest screening dataset available on HER2 overexpression/amplification in this indication. We further analyzed correlation(s) of HER2 overexpression/amplification with clinical and epidemiological factors.
Methods
HER2-positivity was analyzed by histological subtype, tumor location, geographic region, and specimen type. Exploratory efficacy analyses were performed.
Results
The HER2-positivity rate was 22.1 % across analyzed tumor samples. Rates were similar between European and Asian patients (23.6 % vs. 23.9 %), but higher in intestinal- vs. diffuse-type (31.8 % vs. 6.1 %), and gastroesophageal junction cancer versus gastric tumors (32.2 % vs. 21.4 %). Across all IHC scores, variability in HER2 staining (≤30 % stained cells) was observed in almost 50 % of cases, with increasing rates in lower IHC categories, and did not affect treatment outcome. The polysomy rate was 4 %.
Conclusions
HER2 expression varies by tumor location and type. All patients with advanced gastric or gastroesophageal junction cancer should be tested for HER2 status, preferably using IHC initially. Due to the unique characteristics of gastric cancer, specific testing/scoring guidelines should be adhered to.
Objectives This study sought to assess the extent and composition of atherosclerosis contributing to acute coronary syndrome events in women compared with men. Background Pathological studies suggest ...that plaque composition and burden may differ by sex. It is unclear whether sex impacts the extent, characteristics, and potential vulnerability of coronary plaques. Methods A total of 697 patients (24% women) with acute coronary syndromes were enrolled in the prospective, multicenter PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study. Three-vessel multimodality intracoronary imaging (quantitative coronary angiography, grayscale, and radiofrequency intravascular ultrasound IVUS) was performed after treatment of the culprit lesion(s). Events during a median 3.4-year follow-up were ascribed to recurrent culprit versus untreated nonculprit lesions. The authors performed a post hoc, sex-based subgroup analysis. Results Women were older and had more comorbid disease than men. By angiography, women had a similar number of angiographic culprit (p = 0.53) but fewer nonculprit (p = 0.05) lesions, and fewer vessels with nonculprit lesions (p = 0.048) compared with men even after multivariable adjustment (p = 0.002). By IVUS, women had fewer nonculprit lesions (p = 0.002), but similar plaque burden (PB) per lesion (55.6% vs. 55.3%; p = 0.35), and female sex was not predictive of severe (>70%) PB (p = 0.052). Plaque rupture was less common in women (6.6% vs. 16.3%; p = 0.002) even after adjusting for comorbidities (p = 0.004), as was the total necrotic core volume (p < 0.0001). The frequency of other plaque phenotypes was similar for men and women including pathological intimal thickening, thin-cap fibroatheromas (TCFA), and thick-cap fibroatheromas. Rates of major adverse cardiovascular events attributed to culprit and nonculprit lesions at 1-, 2-, and 3-year follow-up were not significantly different between men and women, although women were rehospitalized more frequently due to culprit lesion–related angina. For men, nonculprit lesion minimal lumen area ≤4.0 mm2 , PB ≥70%, and TCFA predicted nonculprit MACE at 3 years, whereas for women, only TCFA and PB were predictive. Conclusions The PROSPECT study validates that despite having more comorbid risk factors than men, women have less extensive coronary artery disease by both angiographic and IVUS measures, and that lesions in women compared with men have less plaque rupture, less necrotic core and calcium, similar plaque burden, and smaller lumens. TCFA may also be a stronger marker of plaque vulnerability in women than men.
Indian hedgehog (IHH) is a secreted signaling molecule of the hedgehog family known to play important roles in the regulation of chondrocyte differentiation, cortical bone formation, and the ...development of joints. Here, we describe that copy-number variations of the IHH locus involving conserved noncoding elements (CNEs) are associated with syndactyly and craniosynostosis. These CNEs are able to drive reporter gene expression in a pattern highly similar to wild-type Ihh expression. We postulate that the observed duplications lead to a misexpression and/or overexpression of IHH and by this affect the complex regulatory signaling network during digit and skull development.
Cerebral embolization during transcatheter aortic valve implantation (TAVI) can lead to a spectrum of clinically relevant manifestations, ranging from overt stroke to mild neurologic or cognitive ...deficits and subclinical cerebral infarcts. This study sought to determine the frequency of neurologic injury, cerebral ischemic lesions, and cognitive dysfunction in subjects undergoing contemporary commercial TAVI in the United States. Neuro-TAVR is the first prospective, multicenter study to use serial systematic neurologic and cognitive assessments and diffusion-weighted magnetic resonance imaging (at 4 ± 2 days after procedure) to investigate the incidence and severity of neurologic injury after contemporary unprotected TAVI in the United States. A total of 44 consecutive patients underwent TAVI at 5 US sites. Diffusion-weighted magnetic resonance imaging lesions were detected in 94%, with a mean of 10.4 ± 15.3 lesions per subject and a median total lesion volume of 295 mm3 (interquartile range 71.6 to 799.6 mm3 ). New neurologic impairment (worsening in National Institutes of Health Stroke Scale score from baseline with new cerebral lesions) occurred in 22.6% (7 of 31) of subjects at discharge and 14.8% (4 of 27) at 30 days. In addition, cognitive decrements from baseline were identified by the Montreal Cognitive Assessment in 33% (12 of 36) of subjects at discharge and 41% (13 of 32) at 30 days. In conclusion, this contemporary cohort of US patients confirms that TAVI results in cerebral infarction in most patients and that 1 in 5 patients have measurable neurologic impairment and 1 in 3 patients have decrease in cognitive measures by Montreal Cognitive Assessment score after TAVI, reinforcing the need for methods to mitigate the risk of brain injury during TAVI.
Data on health status outcomes after spontaneous coronary artery dissection (SCAD) are limited.
Using the Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) study we ...compared patients with SCAD and other acute myocardial infarction (AMI) at presentation (baseline), 1-month, and-12 months using standardized health status instruments. Among 3572 AMI patients ≤ 55 years, 67 had SCAD. SCAD patients were younger (median age (IQR) 45 (40.5-51) years vs. 48 (44-52) in other AMI, p = 0.003), more often female (92.5% vs. 66.6%), have college education (73.1% vs. 51.7%) and household income >$100,000 (43.3% vs. 17.7% (All p<0.001). SCAD patients at baseline had higher mean ± SD Short Form-12 SF-12 physical component scores PCS (48.7±10.2 vs. 43.8±12.1, p<0.001) and mental component scores MCS (49.6±12.4 vs. 45.4±12.5, p = 0.008), and at 12-months PCS (50.1±9.0 vs. 44.3±12.3, p<0.001) and MCS (53±10.1 vs 50.2±11.0, p = 0.045). The Euro-Quality of Life Scale EQ-5D VAS and EQ-5D index scores were similar at baseline, but higher at 12-months for SCAD (EQ-5D VAS: 82.2±10.2 vs. 72.3±21.0, p<0.001; EQ-5D index scores; 90.2±15.3 vs. 83.7±19.8, p = 0.012). SCAD patients had better baseline Seattle Angina Questionnaire SAQ physical limitation (88.8±20.1 vs. 81.2±25.4, p = 0.017). At 12-months SCAD patients had better physical limitation (98.0±8.5 vs. 91.4±18.8, p = 0.007), angina frequency (96.4±8.8 vs. 91.3±16.8, p = 0.018) and quality of life scores (80.7±14.7 vs 72.2±23.2, p = 0.005). Magnitude of change in health status from baseline to 12-months was not statistically different between the groups. After adjustment for time and comorbidities there remained no difference in most health status outcomes.
SCAD patients fare marginally better than other AMI patients on most health status instruments and have similar 12-month health status recovery. Better pre-event health status suggests a need to modify exercise prescriptions and cardiac rehabilitation protocols to better assist this physically active population to recover.
Background
Despite advancements from balloon angioplasty to drug‐eluting stents, primary patency rates after endovascular revascularization of peripheral artery disease have remained inferior ...compared to surgery. Endovascular revascularization has been limited by restenosis and mechanical stent failure. Thus, there is increased research into other nonstent‐based local drug delivery modalities, which can provide an active drug to inhibit restenosis focally and avoid the risk of systemic adverse effects.
Methods
This review will summarize the unique properties of paclitaxel and studies on paclitaxel local delivery for the treatment of peripheral artery disease. A MEDLINE search for relevant peer‐reviewed scientific literature published in English was conducted. Search terms included but were not limited to paclitaxel pharmacodynamics, paclitaxel local drug delivery, and drug eluting balloons, with a focus on the use of paclitaxel in the context of coronary and peripheral vascular disease.
Results
The primary search produced 182 results of which 51 papers were relevant. Of the 51 relevant papers, 27 were original research papers and 24 were either review papers, commentary or opinion papers.
Conclusions
Paclitaxel has several chemical properties, which make it ideal for local drug delivery including its hydrophobicity, ability to concentrate into the arterial intima layer and prolonged effect on cells even after brief exposure periods. Local delivery of paclitaxel via injection catheters, balloon catheters and coated balloons has shown encouraging results in terms of efficacy and safety in small‐scale animal and clinical studies. Additional preclinical and clinical studies are needed to determine the long‐term efficacy and safety of these treatments in humans.
This phase Ib study (NCT00960960) evaluated pictilisib (GDC-0941; pan-phosphatidylinositol 3-kinase inhibitor) plus paclitaxel, with and without bevacizumab or trastuzumab, or in combination with ...letrozole, in patients with locally recurrent or metastatic breast cancer.
This was a three-part multischedule study. Patients in parts 1 and 2, which comprised 3 + 3 dose escalation and cohort expansion stages, received pictilisib (60-330 mg) plus paclitaxel (90 mg/m
) with and without bevacizumab (10 mg/kg) or trastuzumab (2-4 mg/kg). In part 3, patients received pictilisib (260 mg) plus letrozole (2.5 mg). Primary objectives were evaluation of safety and tolerability, identification of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of pictilisib, and recommendation of a phase II dosing regimen. Secondary endpoints included pharmacokinetics and preliminary antitumor activity.
Sixty-nine patients were enrolled; all experienced at least one adverse event (AE). Grade ≥ 3 AEs, serious AEs, and AEs leading to death were reported in 50 (72.5%), 21 (30.4%), and 2 (2.9%) patients, respectively. Six (8.7%) patients reported a DLT, and the MTD and recommended phase II pictilisib doses were established where possible. There was no pictilisib-paclitaxel drug-drug interaction. Two (3.4%) patients experienced complete responses, and 17 (29.3%) patients had partial responses.
Combining pictilisib with paclitaxel, with and without bevacizumab or trastuzumab, or letrozole, had a manageable safety profile in patients with locally recurrent or metastatic breast cancer. The combination had antitumor activity, and the additive effect of pictilisib supported further investigation in a randomized study.
ClinicalTrials.gov, NCT00960960 . Registered on August 13, 2009.
Trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker, has shown clinical activity in single-arm ...studies enrolling patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC) whose disease had progressed on HER2-targeted therapy in the metastatic setting.
Patients (N = 137) with HER2-positive MBC or recurrent locally advanced breast cancer were randomly assigned to trastuzumab plus docetaxel (HT; n = 70) or T-DM1 (n = 67) as first-line treatment until disease progression or unacceptable toxicity. Primary end points were investigator-assessed progression-free survival (PFS) and safety. Key secondary end points included overall survival (OS), objective response rate (ORR), duration of objective response, clinical benefit rate, and quality of life.
Median PFS was 9.2 months with HT and 14.2 months with T-DM1 (hazard ratio, 0.59; 95% CI, 0.36 to 0.97); median follow-up was approximately 14 months in both arms. ORR was 58.0% (95% CI, 45.5% to 69.2%) with HT and 64.2% (95% CI, 51.8% to 74.8%) with T-DM1. T-DM1 had a favorable safety profile versus HT, with fewer grade ≥ 3 adverse events (AEs; 46.4% v 90.9%), AEs leading to treatment discontinuations (7.2% v 34.8%), corrected and serious AEs (20.3% v 25.8%). Preliminary OS results were similar between treatment arms; median follow-up was approximately 23 months in both arms.
In this randomized phase II study, first-line treatment with T-DM1 for patients with HER2-positive MBC provided a significant improvement in PFS, with a favorable safety profile, versus HT.
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