Of Drowning Children and Doubtful Analogies

In this issue of the Hastings Center Report, James Sabin and his colleagues ask what responsibility investigators in a learning health organization have to patients when research—particularly research of which patients might be unaware—illuminates problematic aspects of the patients' care. Sabin and his colleagues were confronted by this question in the midst of designing a randomized controlled trial that sought to determine if an educational intervention targeted at patients with atrial fibrillation and their clinicians reduces underuse of oral anticoagulants. Worried about harm that might befall patients in the control group and fearing that they would be negligent bystanders if they knew these patients were at risk and did nothing, the investigators adopted a “workaround.” But the “workaround,” I suggest, was not a solution to the negligent bystander problem. Nor was it a solution to the problem as I would alternatively frame it—how to address instances of suboptimal patient care identified through research within learning health organizations.     

Patients undergoing recurrent CT exams: assessment of patients with non-malignant diseases,reasons for imaging and imaging appropriateness

To determine percent of patients without malignancy and ≤ 40 years of age with high cumulative radiation doses through recurrent CT exams and assess imaging appropriateness. From the cohort of patients who received cumulative effective dose (CED) of ≥ 100 mSv over a 5-year period, a sub-set was identified with non-malignant disease. The top 50 clinical indications leading to multiple CTs were determined. Clinical decision support (CDS) system scores were analyzed using a widely adopted standard of 1–3 (red) as “not usually appropriate,” 4–6 (yellow) “may or may not be appropriate,” and 7–9 (green) “usually appropriate.” Clinicians reviewed patient records to assess compliance with appropriate use criteria (AUC). 9.6% of patients in our series were with non-malignant conditions and 1.4% with age ≤ 40 years. CDS scores (rounded) were 2% red, 38% yellow, 27% green, and 33% unscored CTs. Clinical society guidelines for CT exams, wherever available, were followed in 87.5 to 100% of cases. AUCs were not available for several clinical indications as also referral guidelines for serial CT imaging. More than half of CT exams were unrelated to follow-up of a primary chronic disease. We are faced with a situation wherein patients in age ≤ 40 years require or are thought to require many CT exams over the course of a few years but the radiation risk creates concern. There is a fair number of conditions for which AUC are not available. Suggested solutions include development of CT scanners with lesser radiation dose and further development of appropriateness criteria.     

Neorickettsia helminthoeca associated lymphoid,enteric, and pulmonary lesions in dogs from Southern Brazil: An immunohistochemical study

Neorickettsia helminthoeca (NH), the agent of salmon poisoning disease or canine neorickettiosis (CN), is a bacterial endosymbiont of the nematode Nanophyetus salmincola, and infections are spreading among specific fish‐eating mammalians. This article describes the pathologic and immunohistochemical findings associated with spontaneous NH‐induced infections in dogs from Southern Brazil. The principal pathologic findings were hypertrophy of Peyer patches and lymphadenopathy with lymphocytic proliferation, chronic interstitial pneumonia, and chronic enteritis associated with positive intralesional immunoreactivity to antigens of NH within macrophages and histiocytes. Positive immunoreactivity against canine parvovirus‐2 (CPV‐2) or/and canine distemper virus was not detected in the evaluated intestinal segments or in the samples from the cerebellum and lungs, respectively, from the dogs evaluated. These findings demonstrated that NH was involved in the enteric, pulmonary, and lymphoid lesions herein described, and provide additional information to confirm the occurrence of this bacterial endosymbiont within this geographical location. It is proposed that chronic pneumonia should be considered as a pathologic manifestation of NH‐induced infections. Additionally, our results show that the occurrences of CN seem to be underdiagnosed in Southern Brazil due to the confusion with the incidence of CPV‐2.     

A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer

Lessons Learned

• The combination of trametinib and sorafenib has an acceptable safety profile, albeit at doses lower than approved for monotherapy.
• Maximum tolerated dose is trametinib 1.5 mg daily and sorafenib 200 mg twice daily.
• The limited anticancer activity observed in this unselected patient population does not support further exploration of trametinib plus sorafenib in patients with hepatocellular carcinoma.

BackgroundThe RAS/RAF/MEK/ERK signaling pathway is associated with proliferation and progression of hepatocellular carcinoma (HCC). Preclinical data suggest that paradoxical activation of the MAPK pathway may be one of the resistance mechanisms of sorafenib; therefore, we evaluated trametinib plus sorafenib in HCC.MethodsThis was a phase I study with a 3+3 design in patients with treatment‐naïve advanced HCC. The primary objective was safety and tolerability. The secondary objective was clinical efficacy.ResultsA total of 17 patients were treated with three different doses of trametinib and sorafenib. Two patients experienced dose‐limiting toxicity, including grade 4 hypertension and grade 3 elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/bilirubin over 7 days. Maximum tolerated dose was trametinib 1.5 mg daily and sorafenib 200 mg twice a day. The most common grade 3/4 treatment‐related adverse events were elevated AST (37%) and hypertension (24%). Among 11 evaluable patients, 7 (63.6%) had stable disease with no objective response. The median progression‐free survival (PFS) and overall survival (OS) were 3.7 and 7.8 months, respectively. Phosphorylated‐ERK was evaluated as a pharmacodynamic marker, and sorafenib plus trametinib inhibited phosphorylated‐ERK up to 98.1% (median: 81.2%) in peripheral blood mononuclear cells.ConclusionTrametinib and sorafenib can be safely administered up to trametinib 1.5 mg daily and sorafenib 200 mg twice a day with limited anticancer activity in advanced HCC.