The Advanced Data Acquisition Model (Adam): A Process Model for Digital Forensic Practice

As with other types of evidence, the courts make no presumption that digital evidence is reliable without some evidence of empirical testing in relation to the theories and techniques associated with its production. The issue of reliability means that courts pay close attention to the manner in which electronic evidence has been obtained and in particular the process in which the data is captured and stored. Previous process models have tended to focus on one particular area of digital forensic practice, such as law enforcement, and have not incorporated a formal description. We contend that this approach has prevented the establishment of generally-accepted standards and processes that are urgently needed in the domain of digital forensics. This paper presents a generic process model as a step towards developing such a generally-accepted standard for a fundamental digital forensic activity–the acquisition of digital evidence

Incidence and Risk Factors of Thromboembolism with Multiple Myeloma in the Presence of Death as a Competing Risk: An Empirical Comparison of Statistical Methodologies

Multiple myeloma (MM) has an inherent high risk of thromboembolic events associated with patient as well as disease- and treatment-related factors. Previous studies have assessed the association of MM-related thromboembolism using “traditional” Kaplan–Meier (KM) and/or Cox proportional hazard (PH) regression. In the presence of high incidence of death, as would be the case in cancer patients with advanced age, these statistical models will produce bias estimates. Instead, a competing risk framework should be used. This study assessed the baseline patient demographic and clinical characteristics associated with MM-related thromboembolism and compared the cumulative incidence and the measures of association obtained using each statistical approach. The cumulative incidence of thromboembolism was 9.2% using the competing risk framework and nearly 12% using the KM approach. Bias in the measures of covariate risk associations was highest for factors related to risk of death such as increased age (75% bias) and severe liver disease (50%) for the Cox PH model compared to the competing risk model. These results show that correct specification of statistical techniques can have a large impact on the results obtained

Targeting the PD-1 Pathway in Pediatric Solid Tumors and Brain Tumors

While remarkable advances have been made in the treatment of pediatric leukemia over the past decades, new therapies are needed for children with advanced solid tumors and high-grade brain tumors who fail standard chemotherapy regimens. Immunotherapy with immune checkpoint inhibitors acting through the programmed cell death-1 (PD-1) pathway has shown efficacy in some chemotherapy-resistant adult cancers, generating interest that these agents may also be helpful to treat certain refractory pediatric malignancies. In this manuscript we review current strategies for targeting the PD-1 pathway, highlighting putative biomarkers and the rationale for investigation of these drugs to treat common pediatric tumors such as sarcoma, neuroblastoma, and high-grade glioma. We summarize the completed and ongoing clinical trial data available, and suggest potential applications for further study

Impact of Time-Varying Treatment Exposures on the Risk of Venous Thromboembolism in Multiple Myeloma

Multiple myeloma (MM) has one of the highest risks of venous thromboembolism (VTE) of all cancers due to pathologic changes and treatment-related exposures. This study assessed the one-year incidence of VTE in newly diagnosed MM and to determine the baseline and time-varying treatment-related factors associated with VTE risk in a U.S.-based cohort. MM patients were identified and age, gender, and baseline comorbidities were determined. Treatment-related exposures included thalidomide derivatives (IMIDs), proteasome inhibitors, cytotoxic chemotherapy, steroids, erythropoietin-stimulating agents (ESAs), stem cell transplants (SCT), hospitalizations, infection, and central venous catheters (CVC). Multiple statistical models were used including a baseline competing risks model, a time-varying exposure Cox proportional hazard (CPH) model, and a case-time-control analysis. The overall incidence of VTE was 107.2 per 1000 person-years with one-half of the VTEs occurring in the first 90 days. The baseline model showed that increasing age, heart failure, and hypertension were associated with one-year incidence of VTE. MM-specific IMID treatment had lower than expected associations with VTE based on prior literature. Instead, exposure to ESAs, SCT, CVC, and infection had higher associations. Based on these results, VTE risk in MM may be less straightforward than considering only chemotherapy exposures, and other treatment-related exposures should be considered to determine patient risk

Afatinib for the Treatment of \u3cem\u3eEGFR\u3c/em\u3e Mutation-Positive NSCLC: A Review of Clinical Findings

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors represent the standard of care in patients with EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). The availability of several EGFR tyrosine kinase inhibitors approved for use in the first-line or later settings in NSCLC warrants an in-depth understanding of the pharmacological properties of, and clinical data supporting, these agents. The second-generation, irreversible ErbB-family blocker, afatinib, has been extensively studied in the context of EGFRm+ NSCLC. Results from the LUX-Lung 3 and 6 studies showed that afatinib was more active and better tolerated than chemotherapy in patients with tumors harboring EGFR mutations. Subanalysis of these trials, along with real-world data, indicates that afatinib is active in patients with certain uncommon EGFR mutations (S768I/G719X/L861Q) as well as common mutations (Del19/L858R), and in patients with active brain metastases. In LUX-Lung 7, a head-to-head phase IIb trial, afatinib improved progression-free survival and time-to-treatment failure versus the first-generation reversible EGFR tyrosine kinase inhibitor, gefitinib, albeit with a higher incidence of serious treatment-related adverse events. Nevertheless, afatinib is generally well tolerated, and adverse events are manageable through supportive care and a well-defined tolerability-guided dose adjustment scheme. In this review, we provide a detailed overview of the pharmacology, efficacy, and safety of afatinib, discuss treatment sequencing strategies following emergence of different resistance mechanisms, and shed light on the economic impact of afatinib. We also provide a comparison of afatinib with the available EGFR tyrosine kinase inhibitors and discuss its position within treatment strategies for patients with EGFRm+ NSCLC

Vena Cava Filter Retrieval Rates and Factors Associated with Retrieval in a Large US Cohort

Background Retrieval of vena cava filters (VCFs) is important for safety as complications increase with longer dwell times. This study assessed VCF retrieval rates and factors associated with retrieval in a national cohort. Methods and Results VCFs were identified by procedural codes from an administrative claims database. Patients were identified who had a VCF placement during a hospitalization from a national commercial administrative claims database. Indications for VCF placement were identified as pulmonary embolism with or without deep vein thrombosis, deep vein thrombosis only, or prophylactic. Patient demographic and clinical characteristics were included in proportional hazard regression models to find associations with early (90-day) and 1-year VCF retrieval. Initiation of anticoagulation and the correlation between time-to-retrieval and time-to-initiation of anticoagulation were observed. Of 54 766 patients receiving a VCF, 36.9% had pulmonary embolism, 43.9% had deep vein thrombosis only, and 19.2% had no apparent venous thromboembolism present. Over the 1 year of follow-up, the cumulative incidence of VCF retrieval was 18.4%. Retrieval increased over time from a low of 14.0% in 2010 up to ≈24% in 2014. In adjusted time-to-event models, increasing age, differing regions, and some comorbidities were associated with poorer retrieval rates. Initiation of anticoagulation was poorly correlated with retrieval, with anticoagulation preceding retrieval by a median of 51 days while those without retrieval had a median of 278 days of exposure to anticoagulation. Conclusions VCF retrieval increased over the study period but remained suboptimal and was weakly correlated with anticoagulation initiation

Risk Stratification for Bleeding Complications in Patients With Venous Thromboembolism: Application of the HAS-BLED Bleeding Score During the First 6 Months of Anticoagulant Treatment

Background—The Hypertension, Abnormal renal/liver function, Stroke, Bleeding, Labile International Normalized Ratio (INR), Elderly, Drugs or alcohol use (HAS-BLED) score has strong predictive validity for major bleeding complications, but limited validation has been conducted in venous thromboembolism (VTE). This study evaluates the HAS-BLED score in a large cohort of VTE patients. Methods and Results—A retrospective cohort of adults ≥ 18 years with primary diagnosis of VTE between January 1, 2010 and November 31, 2013 were identified in an insurance claims database. Patients were tracked until death, any bleed event, or end of study period. HAS-BLED score and components were evaluated via proportional hazard models. Cumulative incidence functions were reported at 30, 60, 90, and 180 days. N=132 280 patients with a VTE were identified, with 73.8% having HAS-BLED scores of 0 to 2, 3.6% score ≥ 4, and 4789 bleeding events (3.6% all patients). A 1-point HAS-BLED score increase was associated with 20% to 30% bleeding rate increase overall, but in a cancer cohort only the increase from 3- to 4-points was significant for all bleeds (csHR=1.41, 95% CI: 1.17-1.69; sdHR=1.40, 95% CI: 1.17-1.69) and major bleeds (csHR=1.66, 95% CI: 1.26-2.20; sdHR=1.66, 95% CI: 1.25-2.19). Adding cancer to the model as an independent covariate provided the strongest association among all covariates, with csHR=2.25 (95% CI: 1.98-2.56) and sdHR=2.11 (95% CI: 1.85-2.41) in the model for major bleeds. Conclusions—The HAS-BLED score has good predictive validity for bleeding risks in patients with VTE. The addition of cancer as an independent bleeding risk factor merits consideration, possibly as part of the B criterion ( bleeding tendency or predisposition )

Multiple Sclerosis Outcomes after Cancer Immunotherapy

INTRODUCTION: Neurological immune-related adverse events are a rare but potentially deadly complication after immune checkpoint inhibitor (ICI) treatment. As multiple sclerosis (MS) is an immune-mediated disease, it is unknown how ICI treatment may affect outcomes. METHODS: We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab 2 years prior their FDA approval until December 31, 2017, to include all cases with confirmed diagnosis/relapse of MS. We also included cases reported in the literature and a patient from our institution. RESULTS: We identified 14 cases of MS with median age of presentation of 52 years. Indications for ICI included melanoma in 7 (36.36%) cases, non-small cell lung carcinoma in 2 (18.18%) cases, 1 case (9.09%) each of pleural mesothelioma, renal cell carcinoma, and colorectal cancer, and unreported in 2 (18.18%) cases. History of MS was confirmed in 8 (57.1%) cases. Median time to beginning of symptoms was 29 days with rapid disease progression; two patients died due to their relapse. Median time for symptom resolution was 8 weeks. Outcomes did not vary by comparing CTLA-4 and PD-1/PD-L1 inhibitors. CONCLUSIONS: Reported MS relapses after ICI are rare, but the adverse events described include rapid neurologic progression and death. Larger and prospective studies are warranted to assess disability and long-term outcomes and outweigh the risks of starting immunotherapy in patients with MS

Edge modes in self-gravitating disc-planet interactions

We study the stability of gaps opened by a giant planet in a self-gravitating protoplanetary disc. We find a linear instability associated with both the self-gravity of the disc and local vortensity maxima which coincide with gap edges. For our models, these edge modes develop and extend to twice the orbital radius of a Saturn mass planet in discs with disc-to-star mass ratio >0.06, corresponding to a Toomre Q < 1.5 at the outer disc boundary. Unlike the local vortex-forming instabilities associated with gap edges in weakly or non-self-gravitating low viscosity discs, the edge modes are global and exist only in sufficiently massive discs, but for the typical viscosity values adopted for protoplanetary discs. Analytic modelling and linear calculations show edge modes may be interpreted as a localised disturbance associated with a gap edge inducing activity in the extended disc, through the launching of density waves excited at Lindblad resonances. Nonlinear hydrodynamic simulations are performed to investigate the evolution of edge modes in disc-planet systems. The form and growth rates of unstable modes are consistent with linear theory. Their dependence on viscosity and gravitational softening is also explored. We also performed a first study of the effect of edge modes on planetary migration. We found that if edge modes develop, then the average disc-on-planet torque becomes more positive with increasing disc mass. In simulations where the planet was allowed to migrate, although a fast type III migration could be seen that was similar to that seen in non-self-gravitating discs, we found that it was possible for the planet to interact gravitationally with the spiral arms associated with an edge mode and that this could result in the planet being scattered outwards. Thus orbital migration is likely to be complex and non monotonic in massive discs of the type we consider.Comment: 26 pages, 21 figures. Accepted by MNRAS. Abstract displayed is shortene