Citations

Abstract Chimeric antigen receptor T (CAR-T) cell therapy is a new pillar in cancer therapeutics; however, its application is limited by the associated toxicities. These include cytokine release syndrome (CRS) and neurotoxicity. Although the IL-6R antagonist tocilizumab is approved for treatment of CRS, there is no approved treatment of neurotoxicity associated with CD19-targeted CAR-T (CART19) cell therapy. Recent data suggest that monocytes and macrophages contribute to the development of CRS and neurotoxicity after CAR-T cell therapy. Therefore, we investigated neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential strategy to manage CART19 cell–associated toxicities. In this study, we show that GM-CSF neutralization with lenzilumab does not inhibit CART19 cell function in vitro or in vivo. Moreover, CART19 cell proliferation was enhanced and durable control of leukemic disease was maintained better in patient-derived xenografts after GM-CSF neutralization with lenzilumab. In a patient acute lymphoblastic leukemia xenograft model of CRS and neuroinflammation (NI), GM-CSF neutralization resulted in a reduction of myeloid and T cell infiltration in the central nervous system and a significant reduction in NI and prevention of CRS. Finally, we generated GM-CSF–deficient CART19 cells through CRISPR/Cas9 disruption of GM-CSF during CAR-T cell manufacturing. These GM-CSFk/o CAR-T cells maintained normal functions and had enhanced antitumor activity in vivo, as well as improved overall survival, compared with CART19 cells. Together, these studies illuminate a novel approach to abrogate NI and CRS through GM-CSF neutralization, which may potentially enhance CAR-T cell function. Phase 2 studies with lenzilumab in combination with CART19 cell therapy are planned.

Summary Cardiac surgery has been shown to be associated with increased risk of acute ischemic stroke. This report presents a case of a successful mechanical embolectomy procedure to treat a patient for an acute ischemic stroke, which was caused by the cardiac embolization of a ‘foreign body’ containing debris following a redo sternotomy procedure for mitral valve replacement and tricuspid valve annuloplasty.

AbstractIntroductionThe easily‐imaged retinal microvasculature may reflect the brain microvasculature and therefore be related to dementia.MethodsIn a population‐based study of 12,482 adults aged 50‐73 years (22% African American), we estimated the relationship of retinal characteristics from fundus photography (1993‐1995) with incident all‐cause dementia (1993‐1995 to 2011‐2013) and with etiologic subtype of dementia/mild cognitive impairment (2011‐13).ResultsA total of 1259 (10%) participants developed dementia over a mean 15.6 years. Moderate/severe (vs. no) retinopathy (hazard ratio [HR], 1.86; 95% confidence interval [CI]: 1.36–2.55) and central retinal arteriolar equivalent (narrowest quartile vs. widest three quartiles; HR, 1.26; 95% CI: 1.09–1.45) were associated with all‐cause dementia. Results were qualitatively stronger (but not statistically significantly different) in participants with diabetes. Retinopathy was associated with a joint outcome of cerebrovascular‐related, but not Alzheimer's disease–related, dementia/mild cognitive impairment (HR, 2.29; 95% CI: 1.24–4.23).DiscussionExploration of measures in the eye may provide surrogate indices of microvascular lesions relevant to dementia.

Context.— The College of American Pathologists proficiency testing program has been instrumental in identifying problems in clinical testing. Objective.— To describe how this program was used to identify a single-nucleotide polymorphism that affects clinical testing for spinocerebellar ataxia type 3. Design.— A proficiency testing sample with discordant results for spinocerebellar ataxia type 3 analysis was further evaluated by targeted Sanger sequencing and genotype polymerase chain reaction using multiple DNA polymerases. Results.— Of 28 laboratories responding in the spinocerebellar ataxia type 3 Proficiency Survey, 18 reported an incorrect homozygous result and 10 reported the expected heterozygous result. A heterozygous single-nucleotide polymorphism complementary to the 3′ end of a published forward primer was identified in the proficiency testing sample, which may have led to allele dropout. However, this primer was used by only 3 of 18 laboratories (16%) reporting a homozygous result. A new forward primer of identical sequence, except for the 3′ end being complementary to the single-nucleotide polymorphism, showed the expected heterozygous pattern. The possibility of DNA polymerase 3′-5′ exonuclease activity contributing to allele dropout was investigated by testing 9 additional polymerases with and without exonuclease activity. No clear pattern emerged, but enzymes with and without 3′-5′ exonuclease activity yielded both homozygous and expected heterozygous results with the published forward primer. Conclusions.— Proactive systematic primer sequence checking is recommended because single-nucleotide polymorphism interference may result in allele dropout and impact clinical testing. Allele dropout is also influenced by other factors, including DNA polymerase exonuclease activity.

The number of survivors of cancer in the United States, already 14.5 million, is growing with improved cancer treatment and aging of the population. Two-thirds of cancer survivors will be older than age 65 and are likely to enter cancer treatment already deconditioned and with multiple comorbidities. Survivors of cancer face numerous adverse consequences of cancer treatment that add to or exacerbate the effects of existing comorbidities and increase risk of functional decline. Many of these problems are amenable to rehabilitation interventions, but referral to cancer rehabilitation professionals is not a standard part of care. We present an expanded prospective model of surveillance, cancer rehabilitation assessment, and referral efforts using a multidisciplinary team approach. In this model, cancer rehabilitation begins at the time of cancer diagnosis and continues through and beyond cancer treatment. Physical impairments and psychosocial symptoms are assessed and treated, and lifestyle and exercise interventions are provided to optimize functioning, health, and quality of life. We present a stepped-care framework to guide decisions on when, how, and where to refer survivors to cancer rehabilitation specialists depending on safety requirements and needs. This model has the potential to result in early identification of symptoms and impairments, appropriate referral and timely treatment, and, in turn, will better address and minimize both acute and long-term cancer morbidity.