Immune-Related Adverse Events and Immune Checkpoint Inhibitor Efficacy in Patients with Gastrointestinal Cancer with Food and Drug Administration-Approved Indications for Immunotherapy.

INTRODUCTION: Immune-related adverse event (IRAE) onset may represent a clinical biomarker for anti-programmed cell death protein 1 (PD-1) antibody response based on emerging evidence from patients with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)-approved indications to receive immune checkpoint inhibitor therapy. MATERIALS AND METHODS: The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti-PD-1 antibodies for FDA-approved indications. The primary and secondary outcomes of the study were progression-free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes. RESULTS: Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached [NR] vs. 3.9 months [hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05-0.3, p < .001]; OS: NR vs. 7.4 months [HR 0.11, 95% CI 0.03-0.36, p < .001]). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset. CONCLUSION: Patients with gastrointestinal cancer who experienced IRAEs while on anti-PD-1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response. IMPLICATIONS FOR PRACTICE: Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno-oncology. Immune-related adverse event onset appears to be one such biomarker. Across tumor types, immune-related adverse event onset has been associated with response to anti-programmed cell death protein 1 (PD-1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti-PD-1 antibodies. Before immune-related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune-related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.

Alternative technique or mitigating strategy for sevoflurane-induced neurodegeneration: a randomized controlled dose-escalation study of dexmedetomidine in neonatal rats.

BACKGROUND: Brain injury in newborn animals from prolonged anaesthetic exposure has raised concerns for millions of children undergoing anaesthesia every yr. Alternative anaesthetic techniques or mitigating strategies are urgently needed to ameliorate potentially harmful effects. We tested dexmedetomidine, both as a single agent alternative technique and as a mitigating adjuvant for sevoflurane anaesthesia. METHODS: Neonatal rats were randomized to three injections of dexmedetomidine (5, 25, 50, or 100 µg kg -1 every 2 h), or 6 h of 2.5% sevoflurane as a single agent without or with dexmedetomidine (1, 5, 10, or 20 µg kg -1 every 2 h). Heart rate, oxygen saturation, level of consciousness, and response to pain were assessed. Cell death was quantified in several brain regions. RESULTS: Dexmedetomidine provided lower levels of sedation and pain control than sevoflurane. Exposure to either sevoflurane or dexmedetomidine alone did not cause mortality, but the combination of 2.5% sevoflurane and dexmedetomidine in doses exceeding 1 µg kg -1 did. Sevoflurane increased apoptosis in all brain regions; supplementation with dexmedetomidine exacerbated neuronal injury, potentially as a result of ventilatory or haemodynamic compromise. Dexmedetomidine by itself increased apoptosis only in CA2/3 and the ventral posterior nucleus, but not in prefrontal cortex, retrosplenial cortex, somatosensory cortex, subiculum, lateral dorsal thalamic nucleaus, or hippocampal CA1. CONCLUSIONS: We confirm previous findings of sevoflurane-induced neuronal injury. Dexmedetomidine, even in the highest dose, did not cause similar injury, but provided lesser degrees of anaesthesia and pain control. No mitigation of sevoflurane-induced injury was observed with dexmedetomidine supplementation, suggesting that future studies should focus on anaesthetic-sparing effects of dexmedetomidine, rather than injury-preventing effects.

The Management and Imaging of Vestibular Schwannomas.

Vestibular schwannomas are the most common cerebellopontine angle tumor. During the past century, the management goals of vestibular schwannomas have shifted from total resection to functional preservation. Current treatment options include surgical resection, stereotactic radiosurgery, and observation. Imaging has become a crucial part of the initial screening, evaluation, and follow-up assessment of vestibular schwannomas. Recognizing and understanding the management objectives, various treatment modalities, expected posttreatment findings, and complications allows the radiologist to play an essential role in a multidisciplinary team by providing key findings relevant to treatment planning and outcome assessment. The authors provide a comprehensive discussion of the surgical management, role of radiation therapy and observation, imaging differential, and pre- and posttreatment imaging findings of vestibular schwannomas.

Testicular torsion: twists and turns.

Testicular torsion is one of the common causes of acute scrotal pain. This review discusses the clinical and sonographic findings of intravaginal and extravaginal testicular torsion, including the normal sonographic and vascular anatomy of the testis. The role of color flow Doppler and spectral Doppler is also emphasized in the patient's complete, incomplete, and intermittent testicular torsion. Sonographic features of testicular torsion mimics, such as vasculitis, venous thrombosis, scrotal edema, and technical parameters, are also presented. A brief description of new developments such as contrast-enhanced ultrasound, dynamic contrast magnetic resonance imaging, and near-infrared imaging is included.

Ier5, a novel member of the slow-kinetics immediate-early genes.

We describe here a novel member of the slow-kinetics immediate-early gene family. Ier5 is an intronless gene, encoding a serum- and growth factor-inducible message of 2123 nucleotides that is present in a wide variety of tissues. The predicted open reading frame encodes a 308-amino-acid, highly proline-rich protein with homology to the amino terminus of the immediate-early gene pip92/Ier2/ETR101. Ier5 is predicted to be a nuclear protein and contains a PEST-like sequence, suggesting rapid protein degradation. Multiple phosphorylation sites are present. Ier5 shows growth factor induction kinetics similar to that of pip92/Ier2/ETR101, but unlike pip92/Ier2/ETR101 does not appear to require phosphokinase C activity for transcriptional activation. The sequence of the promoter region of Ier5 was determined and examined for transcription factor binding sites thought to mediate serum and growth factor response. Multiple AP-1 sites and an Ets-1 site were observed, but the CArG and CArG-like boxes of the serum response element were absent. The predicted nuclear localization of Ier5, coupled with the potential for rapid regulation by phosphorylation and/or degradation, suggests that Ier5 may play an important role in mediating the cellular response to mitogenic signals.