Citations

Purpose There are sparse data defining the dose response of radiation therapy (RT) to the hypothalamus and pituitary in pediatric and young adult patients with brain tumors. We examined the correlation between RT dose to these structures and development of endocrine dysfunction in this population. Materials and Methods Dosimetric and clinical data were collected from children and young adults (< 26 years of age) with brain tumors treated with proton RT on three prospective studies (2003 to 2016). Deficiencies of growth hormone (GH), thyroid hormone, adrenocorticotropic hormone, and gonadotropins were determined clinically and serologically. Incidence of deficiency was estimated using the Kaplan-Meier method. Multivariate models were constructed accounting for radiation dose and age. Results Of 222 patients in the study, 189 were evaluable by actuarial analysis, with a median follow-up of 4.4 years (range, 0.1 to 13.3 years), with 31 patients (14%) excluded from actuarial analysis for having baseline hormone deficiency and two patients (0.9%) because of lack of follow-up. One hundred thirty patients (68.8%) with medulloblastoma were treated with craniospinal irradiation (CSI) and boost; most of the remaining patients (n = 56) received involved field RT, most commonly for ependymoma (13.8%; n = 26) and low-grade glioma (7.4%; n = 14). The 4-year actuarial rate of any hormone deficiency, growth hormone, thyroid hormone, adrenocorticotropic hormone, and gonadotropin deficiencies were 48.8%, 37.4%, 20.5%, 6.9%, and 4.1%, respectively. Age at start of RT, time interval since treatment, and median dose to the combined hypothalamus and pituitary were correlated with increased incidence of deficiency. Conclusion Median hypothalamic and pituitary radiation dose, younger age, and longer follow-up time were associated with increased rates of endocrinopathy in children and young adults treated with radiotherapy for brain tumors.

AbstractBackgroundAlthough the prognosis of core‐binding factor (CBF) acute myeloid leukemia (AML) is better than other subtypes of AML, 30% of patients still relapse and may require allogeneic hematopoietic cell transplantation (alloHCT). However, there is no validated widely accepted scoring system to predict patient subsets with higher risk of relapse.MethodsEleven centers in the US and Europe evaluated 247 patients with t(8;21)(q22;q22).ResultsComplete remission (CR) rate was high (92.7%), yet relapse occurred in 27.1% of patients. A total of 24.7% of patients received alloHCT. The median disease‐free (DFS) and overall (OS) survival were 20.8 and 31.2 months, respectively. Age, KIT D816V mutated (11.3%) or nontested (36.4%) compared with KIT D816V wild type (52.5%), high white blood cell counts (WBC), and pseudodiploidy compared with hyper‐ or hypodiploidy were included in a scoring system (named I‐CBFit). DFS rate at 2 years was 76% for patients with a low‐risk I‐CBFit score compared with 36% for those with a high‐risk I‐CBFit score (P < 0.0001). Low‐ vs high‐risk OS at 2 years was 89% vs 51% (P < 0.0001).ConclusionsI‐CBFit composed of readily available risk factors can be useful to tailor the therapy of patients, especially for whom alloHCT is not need in CR1 (ie, patients with a low‐risk I‐CBFit score).

Objectives: The Bernese periacetabular osteotomy (PAO) is becoming a widely utilized procedure. Patients are younger, highly active, and may desire to return to sport activity. Counseling and managing expectations in these patients is challenging as there is limited information regarding activity level after PAO. The purpose of this study was to analyze physical activity levels after PAO in a large, prospective multicenter cohort. Methods: Assessment of prospectively collected data from a multicenter group included 456 hips treated by PAO for hip dysplasia. After exclusions, 359 hips (80 male, 279 female) remained with a mean age of 25.9 years and mean BMI of 25. Demographics, radiographic measures, and clinical outcomes were evaluated preoperatively, at 1 year follow-up, and at minimum 2 years postoperatively (mean 44.9 months). Activity level was assessed with the University of California-Los Angeles (UCLA) activity score, patients were stratified into low, moderate, and high activity groups based on preoperative function. Descriptive statistics and linear regressions were performed for the primary outcome of change in UCLA. Results: UCLA scores were improved on average 0.6 points at final follow up (p = 0.001). When stratified, the low activity and moderate activity groups had significant improvement in UCLA scores (p<.0001 and p=0007) while the high activity group saw a decrease in UCLA scores (p<.0001). mHHS, HOOS Pain, and HOOS Sports and Recreation scores were significantly improved across all activity levels. Univariable linear regression analysis identified prior ipsilateral surgery, arthroscopy at time of PAO, and preoperative ACEA to be predictors of the change in UCLA score (p<0.05). With the multivariable model, the effect of prior ispilateral surgery was maintained (p = 0.002). Conclusion: The data suggests that improvements in activity level and function can be expected following PAO surgery, with greater gains experienced by patients with lower preoperative level of activity. [Figure: see text][Figure: see text]

Objectives: The incidence of 2nd anterior cruciate ligament (ACL) injury after ACL reconstruction (ACLR) and return to sport (RTS) ranges from 25%-33% in young, active populations; with the greatest risk in the first 12 months after RTS. Recent data indicate that failure to successfully meet traditional RTS criteria, inclusive of strength, functional hop testing and patient reported outcome scores, may identify athletes at increased risk of future injury after ACLR. However, these studies have focused on adult populations and it is unknown if similar RTS criteria apply to young, adolescent, pivoting/cutting athletes. The purpose of this study was to determine if meeting all current, standard RTS criteria would identify young athletes at risk for future ACL injury after primary ACLR and RTS. The tested hypothesis was the likelihood of 2 nd ACL injury in the first 2 years after RTS would be lower in patients who met all RTS criteria prior to initiation of pivoting and cutting activity compared to patients who failed to meet all RTS criteria prior to RTS. Methods: One hundred fifty-nine subjects (112 female, 47 male) with a mean age of 17.2±2.6 years old (range: 13-25 y.o.) underwent ACLR and were released to return to pivoting/cutting sport. These patients were enrolled in a prospective, observational cohort study, completed a RTS assessment and were then tracked for occurrence of 2 nd ACL after ACLR for 24 months. The RTS assessment included 6 tests: isometric quadriceps strength, 4 functional hop tests and the International Knee Documentation Committee (IKDC) patient reported outcome survey. Limb symmetry index (LSI) was calculated for strength and hop test assessments [(involved/uninvolved)*100]. The IKDC was reported on a 0-100 scale with 100 representing a perfect score. Subjects were classified into groups that successfully passed all 6 RTS tests at a level of 90 and again at 95 compared to those that failed to meet all 6 criteria. Chi Square tests were used to determine if successfully passing all 6 RTS measures at various levels of symmetry resulted in a reduced risk of 2 nd ACL injury in the first 24 months after RTS. Results: Thirty-five (22.0%) patients suffered a 2 nd ACL injury, with 26 occurring in the first 12 months after RTS. At the time of RTS, 42 patients (26%) achieved LSI values of 90 or greater on all testing as well as an IKDC value of 90 or greater. The remaining 117 subjects (74%) scored below 90 on at least 1 of the 6 assessments. At this level, there was no difference in 2 nd ACL injury prevalence between patients who passed all RTS criteria (12/42; 28.6%) and those who failed at least 1 criteria (23/117; 19.7%) (p=0.23). When the passing criteria was elevated to 95 on all RTS testing, only 15 subjects (9%) successfully passed all 6 tests. There was no significant difference in 2 nd ACL injury prevalence between patients who passed all RTS criteria (5/15; 33%) and those who failed at least 1 test (30/144; 20.8%) (p=0.32). Sub-group analysis which evaluated the group by graft type, also indicated no significant differences between groups (p>0.05). Conclusion: Current criteria to evaluate readiness to return young athletes to pivoting and cutting sports, using quadriceps strength symmetry, functional hop performance symmetry and patient reported outcomes, may not identify young, active patients at high risk for 2 nd ACL injury. Future work must identify more appropriate criteria to assess readiness to RTS in the young, athletic population and incorporate these findings into practice.

Background Balloon catheter sinuplasty (BCS) for chronic rhinosinusitis (CRS) was found to be successful in adults. The safety and feasibility of BCS in children has been recently established. The purpose of this study was to study the outcome of this technology in CRS in children. Methods A prospective, multicenter, nonrandomized evaluation was performed on patients with CRS. Thirty-two children between the ages of 2 and 11 years were enrolled. Safety was assessed by rate of adverse events. Effectiveness was assessed using the Sino-Nasal (SN)-5 quality-of-life questionnaire for children with CRS at 52 weeks follow-up. Results Thirty-two children were enrolled of which 24 completed their 52 weeks follow-up. No adverse events were reported because of the procedure. SN-5 score improved from a mean of 4.9 at baseline to a mean of 2.95 at 52 weeks (p < 0.0001). Twelve (50%) children had a significant improvement of their SN-5 (> – 1.5), 7 (29%) had moderate improvement (> –1.0 and < –1.5), 2 (8%) had mild improvement (> –0.5 and < –1.0), 1 (4%) remained the same, and 2 (8%) had worsening scores. Conclusions Balloon catheter dilation of the sinus ostia in children was safe and a significant number showed improvement of their SN-5 at 1 year follow-up. Additional studies comparing balloon sinuplasty to other modalities of treatment in children are needed to determine its efficacy in the treatment of CRS in children.

Abstract Purpose: PD-1/L1 axis–directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti–PD-1 response. Experimental Design: Pretreatment tumor biopsies from 166 patients treated with anti–PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery (n = 24) and validation (n = 142) cohorts. Biomarker-positive cells and their colocalization were spatially profiled in pathologist-selected tumor regions using novel Automated Quantitative Analysis algorithms. Selected biomarker signatures, PD-1/PD-L1 interaction score, and IDO-1/HLA-DR coexpression were evaluated for anti–PD-1 treatment outcomes. Results: In the discovery cohort, PD-1/PD-L1 interaction score and/or IDO-1/HLA-DR coexpression was strongly associated with anti–PD-1 response (P = 0.0005). In contrast, individual biomarkers (PD-1, PD-L1, IDO-1, HLA-DR) were not associated with response or survival. This finding was replicated in an independent validation cohort: patients with high PD-1/PD-L1 and/or IDO-1/HLA-DR were more likely to respond (P = 0.0096). These patients also experienced significantly improved progression-free survival (HR = 0.36; P = 0.0004) and overall survival (HR = 0.39; P = 0.0011). In the combined cohort, 80% of patients exhibiting higher levels of PD-1/PD-L1 interaction scores and IDO-1/HLA-DR responded to PD-1 blockers (P = 0.000004). In contrast, PD-L1 expression was not predictive of survival. Conclusions: Quantitative spatial profiling of key tumor-immune suppression pathways by novel digital pathology algorithms could help more reliably select melanoma patients for PD-1 monotherapy. Clin Cancer Res; 24(21); 5250–60. ©2018 AACR.

Objectives: Catecholamine-secreting jugular paragangliomas (JPs) represent a rare subset of head and neck paragangliomas that may present with hypertension, arrhythmia, or syncopal episodes. Subtotal resection to protect critical neurovascular structures may result in persistent catecholamine excess from residual tumor. Herein, we report our experience with stereotactic radiosurgery (SRS) for salvage treatment of catecholamine-secreting JP following subtotal microsurgical resection. Patients: Adult patients treated with SRS after subtotal microsurgical resection of catecholamine-secreting JP. Interventions: SRS. Main Outcome Measures: Post-treatment catecholamine and metanephrine levels, clinical outcomes, and tumor control. Results: Of 85 patients with JPs treated with primary or salvage radiosurgery between 1990 and 2017, 2 (2%) harbored nonmalignant secreting tumors. Patient 1 developed catecholamine excess with elevated norepinephrine (NE) at 475 mcg/24 hours (normal < 80 mcg/24 h). Following subtotal resection, she developed catecholamine excess with radiographic evidence of tumor growth and therefore underwent SRS. Three years post-SRS and beyond, catecholamine levels remained normalized (NE 62 mcg/24 h at 10 yr) and tumor volume remained stable on serial MRI studies over the 17-year follow-up period. Patient 2 developed symptomatic arrhythmia and was found to have a JP. Urine norepinephrine (NE) was elevated at 213 mcg/24 hours. She underwent nerve-sparing subtotal resection and upfront SRS was used to treat residual tumor. Twenty months following SRS, the area of residual JP had not enlarged in size and catecholamine levels remained normal (NE 46 mcg/24 h). Conclusions: Radiosurgery can be used in salvage treatment of catecholamine-secreting JP, providing durable tumor control and resolution of catecholamine excess. For patients with large catecholamine-secreting JP and normal lower cranial nerve function, aggressive nerve-sparing subtotal resection with adjuvant radiosurgery may offer a low-morbidity alternative to gross total resection. Further study of this subset of patients is warranted to substantiate these promising, yet preliminary findings.

Background Perirolandic motor area gliomas present invasive eloquent region tumors within the precentral gyrus that are difficult to resect without causing neurologic deficits. Study Aims This study evaluates the role of awake craniotomy and motor mapping on neurologic outcome and extent of resection (EOR) of tumor in the perirolandic motor region. It also analyzes preoperative risk factors for intraoperative seizures. Methods We evaluated 57 patients who underwent an awake craniotomy for a perirolandic motor area eloquent region glioma. Patients who had positive mapping (PM) or intraoperative identification of motor regions in the cortex using direct cortical stimulation were compared with patients with no positive motor mapping following direct cortical stimulation and negative mapping (NM). Preoperative risks, intraoperative seizures, perioperative outcomes, tumor characteristics, and EOR were also compared. A logistic regression model was used to evaluate the predictors for intraoperative seizures in this patient cohort. Results Overall, 33 patients were in the PM cohort; 24 were in the NM cohort. Our study showed an 8.8% incidence of intraoperative seizures during cortical and subcortical mapping for awake craniotomies in the perirolandic motor area, none of which aborted the case. PM patients had significantly more intraoperative and postoperative seizures (15.5% and 30.3%, respectively) compared with the NM patients (0% and 8.3%, respectively; p = 0.046 and 0.044). New transient postoperative motor deficits were found more often in the PM group (51.5%) versus the NM group (12.5%; p = 0.002). A univariate logistic regression showed that PM (odds ratio [OR]: 1.16; 95% confidence interval [CI], 1.01–1.34; p = 0.035) and preoperative tumor volume (OR: 0.998; 95% CI, 0.996–0.999; p = 0.049) were significant predictors for intraoperative seizures in patients with perirolandic gliomas. Conclusion Awake craniotomies in the perirolandic motor region can be safely performed with a similar incidence of intraoperative seizures as reported for the language cortex. PM in this region may increase the likelihood of perioperative seizures or motor deficits compared with NM. Craniotomies that minimize cortical exposure for perirolandic gliomas that may not localize motor regions can still allow for extensive tumor resection with a good postoperative outcome.