Management of immune-related adverse events resulting from immune checkpoint blockade

Introduction: Immune checkpoint inhibitors (ICI) are now a standard of care in the treatment of many cancers leading to durable responses in patients with metastatic disease. These agents are generally well tolerated but may lead to the occurrence of immune-related adverse events (irAEs). As any organ may be affected, clinicians should be aware of the broad range of clinical manifestations and symptoms and keep in mind that toxicities may occur late, at any point along a patient’s treatment course. Although the most common irAEs are rarely severe, some of them may be associated with great morbidity and even become life-threatening. The rate of occurrence, type and severity of irAEs may vary with the type of ICI; thus, grade 3 and 4 irAEs are reported in more than 55% of patients treated with the combination of ipilimumab 3 mg/kg and nivolumab 1 mg/kg.

Area covered: This review presents the management of irAEs resulting from checkpoint blockade, with a focus on rare irAEs.

Expert commentary: With the development of immuno-oncology and the expanding role of ICI, physicians have learnt to diagnose and treat most of the irAEs that can occur. This review provides an overview of current guidelines, previously published studies and our multidisciplinary team based practices.     

Normal sleep and circadian rhythms: neurobiologic mechanisms underlying sleep and wakefulness.

Sleep is a vital, highly organized process regulated by complex systems of neuronal networks and neurotransmitters. Sleep plays an important role in the regulation of central nervous system and body physiologic functions. Sleep architecture changes with age and is easily susceptible to external and internal disruption. Reduction or disruption of sleep can affect numerous functions varying from thermoregulation to learning and memory during the waking state.     

Genetics of epilepsy: epilepsy research foundation workshop report.

The Sixth Epilepsy Research Foundation workshop, held in Oxford in March 2006, brought together basic scientists, geneticists, epidemiologists, statisticians, pharmacologists and clinicians to consider progress, issues and strategies for harnessing genetics to improve the understanding and treatment of the epilepsies. General principles were considered, including the fundamental importance of clear study design, adequate patient numbers, defi ned phenotypes, robust statistical data handling, and follow-up of genetic discoveries. Topics where some progress had been made were considered including chromosomal abnormalities, neurodevelopment, hippocampal sclerosis, juvenile myoclonic epilepsy, focal cortical dysplasia and pharmacogenetics. The ethical aspects of epilepsy genetics were reviewed. Principles and limitations of collaboration were discussed. Presentations and their matched discussions are produced here. There was optimism that further genetic research in epilepsy was not only feasible, but might lead to improvements in the lives of people with epilepsy.     

Dental Arch and Cephalometric Changes Following Treatment for Class III Malocclusion by Means of the Function Regulator (FR-3) Appliance

AIM: The aim of this retrospective clinical study was to evaluate dental arch, skeletal, dentoalveolar, and soft tissue profile changes following treatment of Class III malocclusion by means of the Function Regulator (FR-3) appliance. SUBJECTS AND METHODS: The study sample consisted of 14 growing patients (seven boys and seven girls) with a mean age of 9.7 +/- 1.1 years presenting Class III malocclusion. They were treated with an FR-3 appliance exclusively for a period of 2.4 +/- 0.6 years. Dental casts and lateral cephalometric radiographs were obtained immediately before initiation and after completion of treatment with the FR-3 appliance. Thirteen variables were used for the dental cast analysis and 61 variables for the cephalometric analysis. The paired t-test was utilized to evaluate the presence of significant changes (p < 0.05). RESULTS: The evaluation of the dental casts revealed that there was a significant increase in intermolar, interpremolar, and intercanine width of the maxilla and of palatal height after treatment. Concerning the mandible, an increase in intermolar and intercanine width and a decrease in lower arch depth were observed. Cephalometric evaluation revealed a significant decrease in SNB angle and an increase in ANB angle, overjet, facial convexity, nose prominence, and lower soft tissue face height. There was an increase in upper lip thickness and a decrease in lower lip convexity observed after treatment. CONCLUSIONS: The results of this study confirm a favorable functional and esthetic maxillary and mandibular position following treatment by means of the function regulator (FR-3) appliance.     

Accuracy of single-time, multilevel registration in image-guided spinal surgery.

BACKGROUND CONTEXT: Computerized frameless stereotactic image-guidance has been used in recent years to improve the accuracy and safety of pedicle screw placement during spine surgery. Because the possibility of intervertebral motion exists, and because the patient is usually in a different position when preoperative imaging is performed compared with the operative position, it has been suggested that the imaging model of the complete lumbar spine and the surgically exposed lumbar spine may be significantly discordant. Consequently, current protocols suggest registering each spinal level (single-level registration) separately before pedicle screw placement at that level, a time-consuming process. PURPOSE: To assess the accuracy of single-time multilevel registration for multilevel pedicle screw placement during image-guided, computer-assisted spine surgery, in the setting of degenerative disorders of the lumbar spine. STUDY DESIGN/SETTING: This is a prospective clinical and radiological study of 45 patients with degenerative disorders of the lumbar spine who underwent instrumented fusion with the use of single-time multilevel registration computer-assisted, image-guided tomography. The accuracy of the pedicle screws placement was confirmed on the basis of a protocol that included intraoperative spontaneous electromyographic (EMG) recordings, direct pedicle visualization, and computer tomography (CT) scans when clinically indicated during the follow-up period. PATIENT SAMPLE: Forty-five consecutive patients who fulfilled the criteria of computer-assisted, image-guided tomography pedicle screw placement for degenerative lumbar spine disease without overt instability. OUTCOME MEASURES: The principal outcome measure was the accuracy of pedicle screw placement with single-time multilevel registration for multilevel pedicle screw placement during image-guided, computer-assisted spine surgery; postoperative CT performed for clinical indications during the follow-up course was used for the assessment of pedicle screw placement. METHODS: Patients were assessed clinically before and after the operation. Data from 45 consecutive cases of image-guided, computer-assisted lumbar spinal fusion were statistically analyzed to determine the relationship between the number of levels registered during single-time registry and the mean registration error (MRE). Intraoperative spontaneous EMG, direct visualization, and postoperative CT scans were used to assess the accuracy of pedicle screw insertion. RESULTS: None of the patients involved in this study experienced clinical sequelae of improper pedicle screw placement. MREs after surface mapping and after point merge were small (less than 1.00 mm and less than 3.00 mm, respectively). During the intraoperative assessment of the pedicle screws placement, no significant spontaneous EMG activity was recorded and the pedicular walls were found intact in direct visualization. The postoperative CT scans showed in 10 patients accurate placement in 55 of the 57 pedicle screws with expansion of the medial wall in two screws. CONCLUSIONS: Single-time, multilevel registration may decrease operative time relative to repeated, single-level registrations, without compromising the increased accuracy of pedicle screw placement afforded by this technique in the setting of degenerative disorders of the lumbar spine. Despite the advantages in computer-guided image surgery, cautious application in the individual patient is recommended until more comprehensive data can be gathered in specific degenerative pathology with overt instability; thus the knowledge of the anatomy remains crucial.     

Antegrade interlocking nailing of humeral shaft fractures

The results of 39 humeral shaft fractures (37 patients) treated with antegrade locked nailing using a Russell–Taylor nail were reviewed. There were 30 acute fractures, 6 fractures malaligned in a hanging cast or brace, and 3 pathological fractures. Patient age ranged from 26 to 80 years (average, 59.7 years) and average follow-up was 25.7 months (range, 6–48 months). Fracture union was achieved in 92.3% of our cases, while shoulder function was excellent or good in 87.2% of cases. Antegrade locked nailing offers a dependable solution for the treatment of humeral shaft fractures, especially in polytrauma patients and cases of segmental or pathological fractures. Far less satisfactory results were obtained in comminuted fractures of the proximal third in the humerus, especially in osteoporotic patients, and we therefore advocate caution with the use of intramedullary nailing in this type of fracture. Certain technical aspects such as avoiding nailing the fracture in distraction, properly countersinking the tip of the nail, and achieving adequate fixation stability have been found to be of paramount importance to reduce the incidence of delayed union/non-union rate and to obtain better functional results from the shoulder joint.