Optimizing T-cell receptor avidity with somatic hypermutation

Adoptive transfer of T cells that have been genetically modified to express an antitumor T-cell receptor (TCR) is a potent immunotherapy, but only if TCR avidity is sufficiently high. Endogenous TCRs specific to shared (self) tumor-associated antigens (TAAs) have low affinity due to central tolerance. Therefore, for effective therapy, anti-TAA TCRs with higher and optimal avidity must be generated. Here, we describe a new in vitro system for directed evolution of TCR avidity using somatic hypermutation (SHM), a mechanism used in nature by B cells for antibody optimization. We identified 44 point mutations to the Pmel-1 TCR, specific for the H-2D^b-gp100_25-33 melanoma antigen. Primary T cells transduced with TCRs containing two or three of these mutations had enhanced activity in vitro. Furthermore, the triple-mutant TCR improved in vivo therapy of tumor-bearing mice, which exhibited improved survival, smaller tumors and delayed or no relapse. TCR avidity maturation by SHM may be an effective strategy to improve cancer immunotherapy.     

Abdominal stab wound injury in children: Do we need a different approach?

Background

Penetrating stab wounds in children are relatively rare and no clear recommendations for the optimal evaluation have been devised. An acceptable traditional approach to the patient with an abdominal stab wound who does not require urgent surgery is selective nonoperative management and serial exams. The use of routine computed tomography remains an actively utilized investigation for these patients at many institutions.

Complications in Intermediate Uveitis: Prevalence,Time of Onset,and Effects on Vision in Short-Term and Long-Term Follow-Up

Purpose: To study the prevalence and time of onset of ocular complications in intermediate uveitis (IU) and to assess their effects on visual outcome in short-term and long-term follow-up.

Methods: A retrospective cohort study of patients with IU who had a minimal follow-up of one year.

Results: 96 patients (174 eyes, 70% females) were included with a mean age at presentation of 30 years. Children constituted 38% of all patients. Mean follow- up was 64.9 months. Pars planitis was the most common form followed by sarcoidosis and multiple sclerosis. Cystoid macular edema (CME), cataract, epiretinal membrane and posterior synechiae were the most prevalent complications. Posterior synechiae, band keratopathy, cataract and papillitis at presentation were associated with worse presenting visual acuity (VA). Of the late-onset complications, glaucoma/ocular hypertension (OHT) was the most significantly associated with worse long-term VA. Most sight-threatening complications (namely CME and glaucoma) were diagnosed at presentation while late complications predominantly affected the posterior segment and included among others peripheral retinal elevations, vasoproliferative tumors, and vitreous hemorrhage. Median LogMAR VA improved at short-term and long-term follow-up, from 0.2 to 0.1 (p<0.001). Subgroup analysis revealed significant VA improvement for eyes with all the different complications except for eyes with glaucoma/OHT.

Conclusion: IU is a chronic low-grade uveitis that may be associated with protean early and late complications of the anterior or posterior segments or both. Optimal treatment regimens are imperative for the strict control of inflammation and proper management of complications thus allowing a favorable long-term prognosis.     

Sleep Apnea and Atrial Fibrillation: Role of the Cardiac Autonomic Nervous System

Sleep apnea is highly associated with atrial fibrillation (AF), and both diseases are highly prevalent in the United States. The mechanistic underpinnings that contribute to their association remain uncertain, but numerous possible mechanisms have been proposed, including dysfunction of the cardiac autonomic nervous system (ANS). Studies have reported that apnea induces hyperactivity of the ANS, leading to increases in AF susceptibility. This review compiles the latest evidence on the role of the ANS in sleep-apnea-induced AF.     

Is computed tomography cystography indicated in children with pelvic fractures?

Purpose: Pelvic fracture evaluation with abdominopelvic computed tomography (CT) and formal CT cystography for rule out of urine bladder injury have been commonly employed in pediatric trauma patients. The additional delayed imaging required to obtain optimal CT cystography is, however, associated with increased doses of ionizing radiation to pelvic organs and represent a significant risk in the pediatric population for future carcinogenic risk. We hypothesized that avoidance of routine CT cystography among pediatric pelvic fracture victims would not result in an appreciable rate of missed bladder injuries and would aid in mitigating the radiation exposure risk associated with these additional images. Methods: A retrospective cohort study involving blunt trauma pelvic fractures among pediatric trauma patients (age<14) between the years 1997 and 2016 was conducted utilizing the Israeli National Trauma Registry. Statistical analysis was performed using SAS statistical software version 9.4 via the tests of Chisquare test and two-sided Fisher''s exact test. A p value of less than 0.05 was considered statistically significant. Results: A total of 1072 children were identified from the registry for inclusion. Mean age of patients was 7.7 years (range 0-14) and 713 (66.5%) were male. Overall mortality in this population was 4.1% (44/1072). Only 2.1% (23) of pediatric patients with pelvic fractures had bladder injury identified, with just 9 children having intraperitoneal bladder rupture (0.8% of all the patients). Conclusion: The vast majority of blunt pediatric trauma victims with pelvic fractures do not have urine bladder injuries. Based on our study results we do not recommend the routine utilization of CT cystography in this unique population.     

Are there gender-specific differences in pregnancy outcome and placental abnormalities of pregnancies complicated with small for gestational age?

Archives of Gynecology and Obstetrics - Adaptations to pathological intrauterine environment might differ in relation to fetal gender. We aimed to study sex-specific differences in placental...     

The efficacy and toxicity of immune checkpoint inhibitors in a real-world older patient population

ImportanceImmunotherapy has emerged as an effective treatment option for the management of advanced cancers. The effects of these immune checkpoint inhibitors in the older patient population has not been adequately assessed.ObjectiveTo understand the impact of aging on CTLA-4 and PDL-1 inhibitors efficacy and immune-related adverse events (irAE) in the context of real-world management of advanced solid cancers.Design, Setting, and ParticipantsThis retrospective study involved all non-study patients with histologically-confirmed metastatic or inoperable solid cancers receiving immunotherapy at Kingston Health Sciences Centre. We defined ‘older patient’ as age ≥ 75. All statistical analyses were conducted under SPSS IBM for Windows version 24.0.Main Outcomes and MeasuresStudy outcomes included immunotherapy treatment response, survival, as well as number, type, and severity of irAEs.ResultsOur study (N = 78) had 29 (37%) patients age <65, 26 (33%) patients age 65–74, and 23 (30%) patients age ≥75. Melanoma, non-small cell lung cancer, and renal cell carcinoma accounted for 70%, 22%, and 8% of the study population, respectively. Distributions of ipilimumab (32%), nivolumab (33%), and pembrolizumab (35%) were similar in the study. The response rates were 28%, 27%, and 39% in the age <65, age 64–74, age ≥75 groups, respectively (P = 0.585). Kaplan-Meier curve showed a median survival of 28 months (12.28–43.9, 95% CI) and 17 months (0–36.9, 95% CI) in the age <65 and age 64–74 groups, respectively; the estimated survival probability did not reach 50% in the age ≥75 group (P = 0.319). There were no statistically significant differences found in terms of irAEs, multiple irAEs, severity of grade 3 or higher, types of irAEs, and irAEs resolution status when comparing between different age groups.Conclusion and RelevanceOur results suggest that patients age ≥75 are able to gain as much benefit from immunotherapy as younger patients, without excess toxicity. Our findings suggest that single agent immunotherapy is generally well-tolerated across different age groups with no significant difference in the type, frequency or severity of irAEs. Future studies evaluating aging and combination immunotherapy are warranted.