Citations

SummaryIbrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B‐cell malignancies. In ibrutinib clinical studies, low‐grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (N = 1768), including 4 randomised controlled trials (RCTs). Rates of any‐grade bleeding were similar for single‐agent ibrutinib and ibrutinib combinations (39% and 40%). Low‐grade bleeding was more common in ibrutinib‐treated than comparator‐treated patients (35% and 15%), and early low‐grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13 months vs. 6 months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person‐months). MH led to treatment discontinuation in 1% of all ibrutinib‐treated patients. Use of anticoagulants and/or antiplatelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure‐adjusted relative risk for MH in both the total ibrutinib‐treated population (1.9; 95% confidence interval, 1.2–3.0) and RCT comparator‐treated patients (2.4; 95% confidence interval, 1.0–5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B‐cell malignancies.

Background There is little data regarding postoperative outcomes of patients with obstructive sleep apnea (OSA) undergoing skull base surgery. The purpose of this study is to determine an association between risk factors and proximity of cerebrospinal fluid (CSF) leak to surgery in patients with OSA undergoing endoscopic skull base surgery. Methods A retrospective review of neurosurgical inpatients, with and without OSA, at a tertiary care institution from 2002 to 2015 that experienced a postoperative CSF leak after undergoing endoscopic skull base surgery. Results Forty patients met inclusion criteria, 12 (30%) with OSA. OSA patients had significantly higher body mass index (BMI; median 39.4 vs. 31.7, p < 0.01) and were more likely to have diabetes (41.7 vs. 10.7%, p = 0.04) than non-OSA patients; otherwise there were no significant differences in clinical comorbidities. No patients restarted positive pressure ventilation (PPV) in the inpatient setting. The type of repair was not a significant predictor of the time from surgery to leak. Patients with OSA experienced postoperative CSF leak 49% sooner than non-OSA patients (Hazard Ratio 1.49, median 2 vs. 6 days, log-rank p = 0.20). Conclusion Patients with OSA trended toward leaking earlier than those without OSA, and no OSA patients repaired with a nasoseptal flap (NSF) had a leak after postoperative day 5. Due to a small sample size this trend did not reach significance. Future studies will help to determine the appropriate timing for restarting PPV in this high risk population. This is important given PPV's significant benefit to the patient's overall health and its ability to lower intracranial pressure.

Heřmanský–Pudlák syndrome (HPS), a rare autosomal recessive disorder, manifests with oculocutaneous albinism and a bleeding diathesis. However, severity of disease can be variable and is typically related to the genetic subtype of HPS; HPS type 6 (HPS‐6) is an uncommon subtype generally associated with mild disease. A Caucasian adult female presented with a history of severe bleeding; ophthalmologic examination indicated occult oculocutaneous albinism. The patient was diagnosed with a platelet storage pool disorder, and platelet whole mount electron microscopy demonstrated absent delta granules. Genome‐wide SNP analysis showed regions of homozygosity that included the HPS1 and HPS6 genes. Full length HPS1 transcript was amplified by PCR of genomic DNA. Targeted next‐generation sequencing identified a novel homozygous missense variant in HPS6 (c.383 T > C; p.V128A); this was associated with significantly reduced HPS6 mRNA and protein expression in the patient's fibroblasts compared to control cells. These findings highlight the variable severity of disease manifestations in patients with HPS, and illustrate that HPS can be diagnosed in patients with excessive bleeding and occult oculocutaneous albinism. Genetic analysis and platelet electron microscopy are useful diagnostic tests in evaluating patients with suspected HPS.Clinical Trial registration:Registrar: ClinicalTrials.govWebsite: www.clinicaltrials.govRegistration Numbers: NCT00001456 and NCT00084305.

Background Computed tomography (CT) of the paranasal sinuses is the diagnostic reference standard for chronic rhinosinusitis and related inflammatory sinus pathology. Nasal nitric oxide (nNO) levels have been investigated as a diagnostic tool in sinus disease because it decreases with sinus obstruction. Objective The primary aim of the study was to determine the correlation of passive (baseline) and dynamic (humming) nNO to CT findings of sinus inflammation and to sinonasal symptoms measured by the modified Sinonasal Outcome Test (26 items) (SNOT-26). Methods From June 2015 through January 2016, subjects had baseline and humming nNO levels measured with a chemiluminescence NO analyzer, and each subject underwent CT imaging and completed the SNOT-26 survey. CT images were scored using the Lund–Mackay (LM) system (LM scores >3 indicated sinus inflammation). Correlation was measured by linear and ordinal regression analysis that compared SNOT-26 scores, LM scores, and nNO measurements. Results Fourteen subjects were recruited. LM scores had a positive pairwise correlation with total SNOT-26 scores ( R 2 = .1457; correlation = .3817) and nasal-specific SNOT-26 scores ( R 2 = .4036; correlation = .6353). Baseline nasal nNO scores had a negative pairwise correlation with LM scores ( R 2 = .1580; correlation = −.3582), total SNOT-26 scores ( R 2 = .1515; correlation = −.3893), and nasal-specific SNOT-26 scores ( R 2 = .0805; correlation = −.4343). Although baseline nNO levels correlated with LM and SNOT-26 scores, humming nNO levels did not show a similar correlation. Conclusion Baseline passive nNO may be a useful and inexpensive point-of-care screening test for sinonasal opacification.

10512 Background: Inotuzumab ozogamicin (InO), a CD22-targeting antibody linked to calicheamicin demonstrated exceptional activity in R/R ALL in adults. InO has been available to pediatric patients with R/R ALL via a compassionate access program. Methods: Participating international pediatric oncology centers received IRB approval to submit retrospective demographic, outcome and toxicity data on pediatric patients who received at least one dose of InO. Results: Thirty-four patients, age 2.3-21.4 yrs (median 11.7) received 1-4 cycles (3 weekly doses) of InO. Patients were heavily pretreated in 1st-5threlapse; 28 were refractory to their preceding regimen. Thirteen patients had prior hematopoietic stem cell transplant (HSCT), 27 received prior CD19 and 8 prior CD22-directed therapy. Pre-InO disease was M3 ( > 25% blasts) in 26 patients, M2 (5-25%) in 3, and MRD only in 5 (1 with extramedullary disease). Of 29 patients with M2/M3 disease at baseline, 18 (62%) achieved a complete remission (CR), 13 of whom were MRD negative. Post-InO, 15 patients proceeded to HSCT and 5 to CAR T-cell therapy. Alterations in CD22 expression at subsequent relapse were noted in two patients with available blasts samples. No deaths were attributed to InO during therapy. The incidence of grade 3/4 infections was 38% and were of the expected types. Grade 1-4 hepatic toxicity was noted in 11/34 (32%) patients, primarily asymptomatic elevations in transaminases/bilirubin. There was no sinusoidal obstruction syndrome (SOS) during InO therapy but 8/15 patients who received HSCT post-InO developed SOS. One patient died from SOS, but the others recovered. The incidence of SOS was higher in patients who had undergone prior HSCT (6/8) versus no prior HSCT (2/7). SIRS (1), neurotoxicity (2) and hemorrhage (3) were infrequent. Three patients had musculoskeletal pain associated with edema. Conclusions: Single agent InO had a CR rate of 62% in heavily pretreated pediatric patients. Toxicities were similar to adults with hepatic and infectious toxicity being the most common. Overall InO was well tolerated, but the incidence of SOS was high in patients who underwent HSCT post-InO, particularly in those who had undergone a prior HSCT.