Sorafenib for the treatment of breast cancer

Introduction: Breast cancer treatment includes many options depending on the tumor clinicopathological profile, which groups breast cancer into various subtypes. Bevacizumab is currently the only drug capable of targeting angiogenesis in breast cancer. Sorafenib has also been studied in combination with other agents.

Areas covered: Pharmacological aspects of sorafenib, including results from preclinical studies on breast cancer cells; findings about clinical efficacy and safety in both single-arm and randomized clinical trials; ongoing trials.

Expert opinion: Since sorafenib as a single agent has shown limited efficacy in breast cancer, its combination with other drugs is under investigation. Dose reduction is the main challenge when sorafenib is combined with chemotherapy or endocrine therapy. Although randomized phase-II trials on sorafenib plus chemotherapy versus chemotherapy alone have shown potential benefits in progression-free survival, preliminary results from a phase-III study in combination with capecitabine are negative. The definitive results of this trial and results from other ongoing phase-II trials will determine further developments of sorafenib in breast cancer. Although these additional data could help determine the most appropriate dose, drug combination and patient settings, a confirmation of the preliminary negative results reported in the phase-III trial are likely to discourage further use of sorafenib in breast cancer, given its non-negligible toxicity, lack of predicting markers, and the number of more promising drugs for breast cancer.     

Judging experts: Australian magistrates’ evaluations of expert opinion quality

Expert opinions admitted by courts are not always valid and reliable. However, we know little about how indicators of opinion quality affect the persuasiveness of an expert. In this study 25 Australian magistrates and 22 jury-eligible lay people rated the persuasiveness (via credibility, value and weight) of either a high- or a low-quality expert opinion. Opinion quality was determined using attributes specified in the Expert Persuasion Expectancy (ExPEx) framework: Field, Specialty, Ability and Trustworthiness. Both magistrates and jurors were significantly more persuaded by the high- than the low-quality expert opinion. Magistrates were also significantly more sceptical of the expert opinion than lay people, and when given the opportunity sought information that was logically relevant to their decision. These results suggest that magistrates can differentiate between high- and low-quality expert opinions, but it is unclear whether the information they need for the task is actually available for use during trials.Key words: expert evidence, expert testimony, forensic science, judges, jury decision-making, persuasion

Expert evidence is regularly used to assist courts with decision-making (Gross, 1991; Jurs, 2015). However, the quality of expert opinions has been, and continues to be, of significant concern (Edmond & San Roque, 2012; Findley, 2008; Martire & Edmond, 2016; National Research Council, 2009; President’s Council of Advisors on Science and Technology, PCAST, 2016; Risinger, Denbeaux, & Saks, 1989). The quality of expert opinions in a range of disciplines has been questioned, including the forensic sciences, mental health diagnoses, medical causation, gender discrimination and eyewitness reliability among others (e.g. Bernstein, 1990; Cole, 2003; Cunliffe & Edmond, 2013; Deitch, 2009; Edens et al., 2012; Imwinkelried, 2009; Martire & Kemp, 2011; Monahan, Walker, & Mitchell, 2008; Taupin, 2004). Even so, the opinions of experts from these and other areas remain persuasive to factfinders.Courts worldwide have been influenced by the mistaken and inaccurate opinions of expert witnesses. False and flawed expert testimony has contributed to approximately 60% of known wrongful convictions identified by the United States Innocence Project (Garrett, 2017; Garrett & Neufeld, 2009), one third (31%) of 71 Australian exonerations (Dioso-Villa, 2015) and one quarter (24%) of exonerations in the United States National Registry of Exonerations (Gross & Shaffer, 2012). Indeed, discredited and unvalidated forms of expert evidence continue to be admitted and relied on by courts despite authoritative criticism (National Research Council, 2009; PCAST, 2016; Skene, 2018). This leaves factfinders with the challenging task of differentiating between witnesses who are genuine experts and those who are not.In Australia, expert evidence is most likely to be evaluated by judicial officers rather than lay juries. Of 592,455 finalised defendants in 2017–2018, 92% (or 545,251) appeared in the Magistrates’ Courts (Australian Bureau of Statistics, ABS, 2019). Magistrates’ Courts are summary courts, meaning that magistrates rather than juries determine the verdict. They also generally consider matters of a less serious nature than the Higher Courts. However, this does not remove the need for expert witnesses. In 2017–2018, Australian Magistrates’ Courts resolved 40,576 theft offences, 56,638 illicit drug offences and 71,405 regulatory driving offences (Australian Bureau of Statistics, 2019). These matters often require the testimony of, for example, fingerprint analysts, forensic chemists, pharmacologists or toxicologists to assist to establish the fact of an offence, or the identity of the perpetrator. Thus it is likely that magistrates regularly hear expert testimony. This makes it important for us to understand how magistrates evaluate expert opinion evidence and whether it can be improved.To date, research examining how judges and magistrates evaluate expert opinion quality suggests that their performance is likely to be imperfect. While there is some evidence that judges evaluating scientific opinions have a good understanding of some key indicators of scientific reliability (i.e. peer review and general acceptance; Gatowski et al., 2001), as well as some types of evidence (i.e. mitochondrial DNA; Hans, 2007), weaknesses have also been found. Judges frequently make logical errors (i.e. the prosecutors’ fallacy; De Keijser & Elffers, 2012), mistakenly believe that scientific knowledge can and should be categorical or certain (Faigman, 2006), misunderstand falsifiability and error rate (Gatowski et al., 2001) and are unable to differentiate valid and invalid research (Kovera & McAuliff, 2000). These failures are likely to impair the assessment of expert quality. However, there are other relevant considerations to be taken into account.At least eight attributes have been identified as logically relevant to determining the quality of an expert opinion (Martire, Edmond & Navarro, 2020; Walton, 1997). These are: Foundation, Field, Specialty, Ability, Opinion, Support, Consistency and Trustworthiness. The indicators of scientific validity and reliability described above relate to Foundation and Ability attributes. Specifically, Foundation covers field, discipline and technique validity and reliability (e.g. error rate, falsifiability, study design, etc.), while Ability relates to the personal proficiency or competence of the witness. Field and Specialty (respectively) relate to the general and specific training, study and experience of the witness relevant to their opinion. Opinion is about the content, conservatism and comprehensibility of the opinion expressed. Support includes the evidentiary basis for, and logic of, the opinion. Consistency concerns whether other experts agree with the opinion. And Trustworthiness incorporates the bias, honesty and conscientiousness of the witness. These attributes have been formalised in the Expert Persuasion Expectancy (ExPEx) framework (Martire et al. 2020) as follows:

1. Foundation – Does training, study or experience in the field F support assertions like A?
2. Field – Does witness W have training, study or experience in the field F?
3. Specialty – Does W have training, study or experience specific to assertions like A?
4. Ability – Does W provide assertions like A accurately and reliably?
5. Opinion – Does W convey A clearly, and with necessary qualifications?
6. Support – Does W rely on evidence in making A?
7. Consistency – Is A consistent with what other experts assert?
8. Trustworthiness – Is W personally reliable as a source?

At present, we have only limited information about the extent to which magistrates and judges attend to and value these logically relevant attributes when assessing the quality of an expert opinion. Champagne, Shuman, and Whitaker (1990) surveyed 10 United States judges who noted a diverse array of attributes relevant to expert quality. These included: credentials (Field or Specialty), bias (Trustworthiness), methodology (Foundation or Support), communication skills (Opinion) and experience (Field or Specialty). Indeed, only one reported attribute clearly fell outside the ExPEx framework – witness demeanour. However, it is not clear whether the attributes that judges believe to be relevant to quality actually influence their evaluation of an expert opinion.More recently, Tadei, Finnila, Reite, Antfolk, and Santtila (2016) surveyed 87 judges in Finland to explore how they determined the quality of an expert opinion. Judges rated the importance of seven listed indicators of reliability: falsifiability (Foundation), error rate (Foundation or Ability), peer-reviewed research (Field or Specialty), scientific acceptance (Foundation), practical acceptance (Consistency), work experience (Field or Specialty) and research activity (Field or Specialty). They were also asked to read five vignettes and note any questions they would ask to evaluate the reliability of the expert opinion in the scenario.The judges’ ratings showed that work experience was seen as the most important of the listed attributes for determining an experts’ reliability. This was followed by error rate, practical acceptance, scientific acceptance, peer-reviewed research, falsifiability and research activity. While 54% of judges also posed questions about error rate in the case scenarios, most of them did not ask about the other listed indicators. Instead, they wanted to know more about the opinion (83%), its basis (77%), and the supporting research (56%). These questions relate to the Opinion, Support and Foundation attributes in ExPEx, respectively.Overall then, we have some preliminary evidence about how judges believe they assess the quality of an expert opinion (Champagne et al., 1990). We also know a little about the information they might seek to complete their assessments (Tadei et al., 2016), and that much of this information is logically relevant to determining the quality of an expert opinion. However, we do not know whether this logically relevant information actually affects the decision-making of judges when it is available.In this article we examine whether the decision-making of magistrates is affected by attributes logically relevant to the quality of the expert opinion. Specifically, we examine whether magistrates consider strong expert opinions more persuasive than weak ones when quality is manipulated via ExPEx attributes. We also compare the performance of magistrates to that of lay people for reference. We predict that magistrates and lay people will be significantly more persuaded by high- rather than low-quality expert opinion evidence when operationalised in terms of ExPEx attributes.In addition, following from Tadei et al. (2016), we examine whether magistrates seek information that is logically relevant to their assessment of expert opinion quality. If magistrates request information that is within the ExPEx framework, rather than outside of it, this suggests that magistrates know which attributes of an expert opinion should be taken into account. It would also indicate that the ExPEx framework usefully represents the informational needs of judges.     

Socioeconomic Trends in Deep Brain Stimulation (DBS) Surgery

Objective: We evaluated trends in deep brain stimulation (DBS) for the 14‐year period from 1993 to 2006. Materials and Methods: We utilized the Nationwide Inpatient Sample data base from the Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. Results: A total of 34,792 patients underwent DBS surgery from 1993 to 2006. There were 756 DBS cases performed in 1993 compared with 4200 DBS procedures performed in 2006. Significant increases in nationwide DBS volume coincided with regulatory approval for new indications—Parkinson's disease and dystonia, respectively. Cost of DBS surgery increased from $38,840 in 1993 to $69,329 in 2006. The majority of cases were done in metropolitan areas (97%) at large academic centers (91%) at a national bill of $291 MM. Conclusions: Future studies will need to include the socioeconomic impact of the technology on disease status, patient access, and costs as it expands to novel indications.     

Endoscopic ultrasound‐guided pelvic abscess drainage (with video)

Pelvic abscesses present a serious and challenging management problem. Endoscopic ultrasound (EUS)‐guided drainage provides a safe and effective minimally invasive treatment option. The likelihood of a successful outcome is dependent on appropriate patient selection, drainage technique and postoperative management. This review outlines the evidence behind and procedural steps required for EUS‐guided pelvic abscess drainage.     

Hierarchy of immunosuppressive strength among myeloid‐derived suppressor cell subsets is determined by GM‐CSF

CD11b⁺/Gr‐1⁺ myeloid‐derived suppressor cells (MDSC) contribute to tumor immune evasion by restraining the activity of CD8⁺ T‐cells. Two major MDSC subsets were recently shown to play an equal role in MDSC‐induced immune dysfunctions: monocytic‐ and granulocytic‐like. We isolated three fractions of MDSC, i.e. CD11b⁺/Gr‐1^high, CD11b⁺/Gr‐1^int, and CD11b⁺/Gr‐1^low populations that were characterized morphologically, phenotypically and functionally in different tumor models. In vitro assays showed that CD11b⁺/Gr‐1^int cell subset, mainly comprising monocytes and myeloid precursors, was always capable to suppress CD8⁺ T‐cell activation, while CD11b⁺/Gr‐1^high cells, mostly granulocytes, exerted appreciable suppression only in some tumor models and when present in high numbers. The CD11b⁺/Gr‐1^int but not CD11b⁺/Gr‐1^high cells were also immunosuppressive in vivo following adoptive transfer. CD11b⁺/Gr‐1^low cells retained the immunosuppressive potential in most tumor models. Gene silencing experiments indicated that GM‐CSF was necessary to induce preferential expansion of both CD11b⁺/Gr‐1^int and CD11b⁺/Gr‐1^low subsets in the spleen of tumor‐bearing mice and mediate tumor‐induced tolerance whereas G‐CSF, which preferentially expanded CD11b⁺/Gr‐1^high cells, did not create such immunosuppressive environment. GM‐CSF also acted on granulocyte–macrophage progenitors in the bone marrow inducing local expansion of CD11b⁺/Gr‐1^low cells. These data unveil a hierarchy of immunoregulatory activity among MDSC subsets that is controlled by tumor‐released GM‐CSF.     

Quantification of the familial contribution to juvenile idiopathic arthritis

Objective

We previously demonstrated that there is familial aggregation of juvenile idiopathic arthritis (JIA). Using a large JIA cohort, we sought to identify additional clusters of JIA cases and to calculate robust estimates of the relative risk (RR) of JIA in the siblings and cousins of JIA probands. We also estimated the population attributable risk (PAR) of familial factors in JIA.

Methods

A probabilistic record‐linking analysis was performed by matching the records of 862 patients with JIA with the records of ∼7 million individuals in the Utah Population Database (UPDB), a computerized genealogic database. For each patient, 5 control subjects matched for birth year and sex were selected from the UPDB. Specialized software was used to test for familial aggregation of disease, to estimate the magnitude of familial risks, and to identify families at high risk of disease.

Results

We identified 22 founders who had significantly more descendants with JIA than expected (5–13 descendants; P values ranged from <0.0001 to <0.008). The PAR of familial factors for JIA was ∼13%. The RR of JIA in the siblings of patients was significantly increased (11.6, 95% confidence interval [95% CI] 4.9–27.5, P < 2.59 × 10⁻⁸). The RR of JIA in first cousins was also increased (5.82, 95% CI 2.5–13.8, P < 6.07 × 10⁻⁵).

Conclusion

We have identified the largest sets of JIA pedigrees described to date. Approximately 13% of cases of JIA can be attributed to familial factors. Siblings and first cousins of probands with JIA have an increased risk of JIA. The observed decline in the magnitude of risk between siblings and cousins suggests that JIA is influenced by shared genetic factors.

     

Cost-effectiveness of boceprevir or telaprevir for untreated patients with genotype 1 chronic hepatitis C

Randomized controlled trials (RCTs) show that triple therapy (TT) with peginterferon alpha, ribavirin, and boceprevir (BOC) or telaprevir (TVR) is more effective than peginterferon-ribavirin dual therapy (DT) in the treatment of previously untreated patients with genotype 1 (G(1) ) chronic hepatitis C (CHC). We assessed the cost-effectiveness of TT compared to DT in the treatment of untreated patients with G(1) CHC. We created a Markov Decision Model to evaluate, in untreated Caucasian patients age 50 years, weight 70 kg, with G(1) CHC and Metavir F2 liver fibrosis score, for a time horizon of 20 years, the cost-effectiveness of the following five competing strategies: 1) boceprevir response-guided therapy (BOC-RGT); 2) boceprevir IL28B genotype-guided strategy (BOC-IL28B); 3) boceprevir rapid virologic response (RVR)-guided strategy (BOC-RVR); 4) telaprevir response-guided therapy (TVR-RGT); 5) telaprevir IL28B genotype-guided strategy (TVR-IL28B). Outcomes included life-years gained (LYG), costs (in 2011 euros) and incremental cost-effectiveness ratio (ICER). In the base-case analysis BOC-RVR and TVR-IL28B strategies were the most effective and cost-effective of evaluated strategies. LYG was 4.04 with BOC-RVR and 4.42 with TVR-IL28B. ICER compared with DT was €8.304 per LYG for BOC-RVR and €11.455 per LYG for TVR-IL28B. The model was highly sensitive to IL28B CC genotype, likelihood of RVR and sustained virologic response, and BOC/TVR prices. Conclusion: In untreated G(1) CHC patients age 50 years, TT with first-generation protease inhibitors is cost-effective compared with DT. Multiple strategies to reduce costs and improve effectiveness include RVR or genotype-guided treatment. (HEPATOLOGY 2012;56:850-860).