"I Don't Have to be Sick to Still Be Worthy": The Barriers Experienced by Adolescent and Young Adult Cancer Survivors in New Zealand.

Purpose: To identify the spectrum and nature of survivorship barriers experienced by New Zealand's adolescent and young adult (AYA) cancer survivor population. In addition, we explore associations between survivorship barriers and sociodemographic characteristics, cancer type, and day-to-day happiness following the end of treatment. Methodology: Participants were recruited for the online survey from AYA cancer service patient databases. Eligibility criteria included: aged 12-24 years at diagnosis, diagnosed between 2010 and 2019, and completed treatment at least one year prior. The analysis focused on 11 barriers (domains, issues, or concerns) which respondents may have faced during survivorship. Results: Two hundred and eighteen AYA survivors participated in the study. The mean number of impactful survivorship barriers was 2.5 (standard deviation 1.7), with 13 respondents (6.0%) reporting no barriers of concern and 31 (14.2%) reporting 5 or more. A higher number of impactful barriers was associated with lower day-to-day happiness (r = -0.34, p ≤ 0.001). The most commonly identified impactful survivorship barriers were mental health (50.0% of respondents), physical health (43.1%), thinking and memory (33.0%), education and work (27.1%), social life (26.1%), and fertility (22.5%). Subgroup analysis identified significant differences according to gender, age at diagnosis, tumor group, ethnicity, and time since diagnosis. Poor access to health care and unmet needs were common themes. Positive impacts, particularly with regards to family relationships, were also identified. Conclusion: These results will inform initiatives to improve AYA survivorship care in New Zealand. Gaps in service delivery and funding will need to be overcome by utilizing innovative strategies and broad sector engagement.

Visits to the Pediatric Emergency Department for Eye Conditions Before and During the COVID-19 Pandemic.

INTRODUCTION: The use of the emergency department (ED) has been increasing, and many visits occur for non-urgent conditions. A similar trend was found among adult visits to the ED for ocular conditions. In this study we analyzed the impact of sociodemographic factors, presentation timing, and the COVID-19 pandemic on pediatric ED (PED) encounters for ophthalmologic conditions. It is important to identify the multifold factors associated with overutilization of the ED for non-urgent conditions. Caring for these patients in an outpatient clinical setting is safe and effective and could decrease ED crowding; it would also prevent delays in the care of other patients with more urgent medical problems and lower healthcare costs. METHODS: We retrospectively reviewed electronic health records of PED ocular-related encounters at two children's hospitals before (January 2014-May 2018) and during the COVID-19 pandemic (March 2020-February 2021). Encounters were categorized based on the International Classification of Diseases codes into "emergent," "urgent," and non-urgent" groups. We analyzed associations between sociodemographic factors and degrees of visit urgency. We also compared visit frequencies, degrees of urgency, and diagnoses between pre-pandemic and pandemic data. RESULTS: Pre-pandemic ocular-related PED encounters averaged 1,738 per year. There were highly significant sociodemographic associations with degrees of urgency in PED utilization. During the 12-month pandemic timeframe, encounter frequency contracted to 183. Emergent visits decreased from 21% to 11%, while the proportions of urgent and non-urgent encounters were mostly unchanged. The most common pre-pandemic urgent diagnosis was corneal abrasion (50%), while visual disturbance was most common during the pandemic (92%). During both time periods, eye trauma was the most frequent emergent encounter and conjunctivitis was the most common non-urgent encounter. CONCLUSION: Sociodemographic factors may be associated with different types of PED utilization for ocular conditions. Unnecessary visits constitute major inefficiency from a healthcare-systems standpoint. The marked decrease in PED utilization and differing proportions of ocular conditions encountered during the pandemic may reflect a decrease in incidence of many of those conditions by social distancing; these changes may also reflect altered parental decisions about seeking care.

Comparison of OCT imaging in children with foveal hypoplasia born full term versus preterm.

PURPOSE: It is unknown if foveal hypoplasia in full-term born children differs in structure and function from that observed in children born preterm. We compared macular structure and visual function in children with history of prematurity and full-term children diagnosed with foveal hypoplasia. METHODS: We compared three groups of subjects (3-18 years old): (1) full-term hypoplasia (FH, n = 56, gestational age ≥ 36 weeks); (2) preterm hypoplasia (n = 57, gestational age ≤ 31 weeks, birth weight ≤ 1500 g); (3) control (n = 54), full-term normal. Using spectral-domain optical coherence tomography volume-scan images, macular structure within 3 mm of Early-Treatment-Diabetic-Retinopathy-Study circle was segmented. Total, inner, and outer foveal thickness of right eyes were compared. Foveal hypoplasia was graded according to the Leicester Grading System. RESULTS: The mean total foveal thickness in micrometers was 263 ± 19 for the control, 299 ± 30 for the full-term hypoplasia, and 294 ± 28 for the preterm hypoplasia groups (F = 33, p < 0.001). Foveal inner retinal layer thickness differed among groups (p < 0.001), but not in the outer layers (p = 0.10). The full-term hypoplasia group had significantly thicker foveal inner layers (p < 0.05) and greater frequency of higher-grade hypoplasia than the preterm hypoplasia group. LogMAR visual acuity was worse in the full-term hypoplasia group (0.35 ± 0.36) than in the preterm hypoplasia group (0.19 ± 0.27, p < 0.001). CONCLUSION: Fovea was thicker in both hypoplasia groups. The full-term hypoplasia group is associated with more severe structure changes and poorer visual function than the preterm hypoplasia group.

A baby carrier fall leading to intracranial bleeding and multilayered retinal hemorrhages.

Significant intracranial and retinal hemorrhages are often seen in infants with abusive head trauma, although accidental injury and previously undiagnosed medical disorders are important considerations in the differential diagnosis. We present the case of an infant with confirmed accidental trauma sustained from an adult-worn baby carrier fall with superimposed head crush injury, which resulted in significant cranial, intracranial, and retinal findings.

Effect of gestational age at birth, sex, and race on foveal structure in children.

PURPOSE: Premature birth, race, and sex are contributing risk factors for retinopathy of prematurity (ROP) and have long-term impact on children's retinal structure. Few studies investigate impact of race and sex on macular structure in children born preterm. This study compared foveal structure in preterm and full-term children. METHODS: Children aged 4-18 years were enrolled into three groups: (1) ROP-risk group (n = 81), born at < 32 weeks gestational age with and without history of ROP; (2) preterm group (n = 46), born at 32-36 weeks gestational age; and (3) control group (n = 68) with full-term birth. Using spectral-domain optical coherence tomography volume-scan images, foveal structure within 1-mm and 3-mm early treatment diabetic retinopathy study circular grid was measured and segmented. Total inner and outer retina thickness of the right eye was compared among the three groups. RESULTS: The mean total foveal thickness (in microns) was 287 ± 26 for the ROP-risk group, 276 ± 19 for the preterm group, and 263 ± 20 for the control group (F = 26, p < 0.001). Foveal thickness of the ROP-risk group was significantly higher than that of the preterm group and the control group (all p < 0.05). Foveal thickness was thinner in black children than in white children and thinner in females than in males (all p < 0.001). A similar disparity in race and sex was found in the thickness of the inner and outer layers. CONCLUSIONS: The fovea was significantly thicker in the ROP-risk group than the control group. Foveal thickness decreases with increased gestational age. Race and sex are significant factors in foveal structure in children.

Do extremely preterm infants need retinopathy of prematurity screening earlier than 31 weeks postmenstrual age?

OBJECTIVE: To evaluate the utility of screening all extremely preterm infants for retinopathy of prematurity (ROP) at 4 weeks chronologic age, which is earlier than recommended by the 2018 AAP guidelines. STUDY DESIGN: Retrospective analysis of infants <27 weeks gestation from two tertiary NICUs between 2006 and 2018 who survived until first eye examination. RESULTS: 550 infants (gestational age 25.1 ± 1.2 weeks and birth weight 758 ± 323 g) had 1310 examinations performed by 32 weeks postmenstrual age (PMA), and 676 (51.6%) of these were prior to 31 weeks PMA. No examinations in infants prior to 31 weeks PMA met the criteria for laser therapy. Of 87/550 infants (15.8%) who required laser therapy, none did so prior to 32 weeks PMA. CONCLUSIONS: No infants born <27 weeks gestation were found to have severe ROP prior to 31 weeks PMA, supporting the most recent AAP recommendation of initiating ROP screening at 31 weeks PMA for extremely preterm infants.

Using OCT Fixation Shift to Assess Eccentric Fixation in Children With Residual Amblyopia.

Purpose: Eccentric fixation in amblyopia is often estimated grossly without precision. Although the usefulness of optical coherence tomography (OCT) fixation shift in the quantification of eccentric fixation in a small cohort of amblyopic children was recently reported, there is a lack of understanding of characteristics of OCT fixation shift. In a retrospective cohort study, we evaluated eccentric fixation with OCT in a large cohort of children with residual amblyopia. Methods: Children, age 4 to 17 years, with residual amblyopia (amblyopic, n = 56) and without amblyopia (control, n = 75) were enrolled. Amblyopia was associated with anisometropia alone (anisometropia subtype, n = 28) and strabismus without or with anisometropia (strabismic subtype, n = 28). Spectral domain OCT was used to estimate fixation. The OCT fixation shift, defined as the distance between the fovea and the fixation point, was measured and adjusted with calculated axial length and converted into visual degrees. Fixation shift in amblyopic eyes, fellow nonamblyopic eyes, and right eyes of the control group were compared. Fixation shift between the anisometropic and strabismic amblyopia subtypes was also compared. Its correlation with visual acuity was estimated. Results: The mean fixation shift was significantly different: 0.17° ± 0.29° for control right eyes, 0.94° ± 1.24° for amblyopic eyes, and 0.34° ± 0.57° for fellow eyes (χ2 = 23.3; P < 0.001). There was no significant difference between fellow eyes and control eyes (P = 0.11). Fixation shift in amblyopic eyes was significantly correlated with visual acuity (R = 0.44; P < 0.001), and it was significantly smaller in the anisometropic subtype than in the strabismic subtypes (0.34° ± 0.46° vs. 1.54° ± 1.48°, W = 338, P < 0.001). Conclusions: OCT fixation shift can be used both in detection and quantification of eccentric fixation in children with residual amblyopia, especially in those with strabismus. Translational Relevance: OCT fixation shift offers a convenient clinical approach in quantitative evaluation of eccentric fixation in children with strabismic amblyopia.

Artificial intelligence for pediatric ophthalmology.

PURPOSE OF REVIEW: Despite the impressive results of recent artificial intelligence applications to general ophthalmology, comparatively less progress has been made toward solving problems in pediatric ophthalmology using similar techniques. This article discusses the unique needs of pediatric patients and how artificial intelligence techniques can address these challenges, surveys recent applications to pediatric ophthalmology, and discusses future directions. RECENT FINDINGS: The most significant advances involve the automated detection of retinopathy of prematurity, yielding results that rival experts. Machine learning has also been applied to the classification of pediatric cataracts, prediction of postoperative complications following cataract surgery, detection of strabismus and refractive error, prediction of future high myopia, and diagnosis of reading disability. In addition, machine learning techniques have been used for the study of visual development, vessel segmentation in pediatric fundus images, and ophthalmic image synthesis. SUMMARY: Artificial intelligence applications could significantly benefit clinical care by optimizing disease detection and grading, broadening access to care, furthering scientific discovery, and improving clinical efficiency. These methods need to match or surpass physician performance in clinical trials before deployment with patients. Owing to the widespread use of closed-access data sets and software implementations, it is difficult to directly compare the performance of these approaches, and reproducibility is poor. Open-access data sets and software could alleviate these issues and encourage further applications to pediatric ophthalmology.

Comparison of the Prognostic Utility of the Cell Cycle Progression Score for Predicting Clinical Outcomes in African American and Non-African American Men with Localized Prostate Cancer.

BACKGROUND: Better prostate cancer risk stratification is necessary to inform medical management, especially for African American (AA) men, for whom outcomes are particularly uncertain. OBJECTIVE: To evaluate the utility of both a cell cycle progression (CCP) score and a clinical cell-cycle risk (CCR) score to predict clinical outcomes in a large cohort of men with prostate cancer highly enriched in an AA patient population. DESIGN, SETTING, AND PARTICIPANTS: Patients were diagnosed with clinically localized adenocarcinoma of the prostate and treated at The Ochsner Clinic (New Orleans, LA, USA) from January 2006 to December 2011. CCP scores were derived from archival formalin-fixed, paraffin-embedded biopsy tissue. CCR scores were calculated as the combination of molecular (CCP score) and clinical (Cancer of the Prostate Risk Assessment [CAPRA] score) components. INTERVENTION: Active treatment (radical prostatectomy, radiation therapy alone, or radiation and hormone therapy) or watchful waiting. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was progression to metastatic disease. Association with outcomes was evaluated via Cox proportional hazards survival analysis and likelihood ratio tests. RESULTS AND LIMITATIONS: The final cohort included 767 men, of whom 281 (36.6%) were AA. After accounting for ancestry, treatment, and CAPRA in multivariable analysis, the CCP score remained a significant predictor of metastatic disease (hazard ratio [HR] 2.04; p<0.001), and there was no interaction with ancestry (p=0.20) or treatment (p=0.09). The CCR score was highly prognostic (HR 3.86; p<0.001), and as with the CCP score, there was no interaction with ancestry (p=0.24) or treatment (p=0.32). Limitations include the retrospective study design and the use of self-reported ancestry information. CONCLUSIONS: A CCR score provided significant prognostic information regardless of ancestry. The findings demonstrate that AA men in this study cohort appear to have similar prostate cancer outcomes to non-AA patients after accounting for all available molecular and clinicopathologic variables. PATIENT SUMMARY: In this study we evaluated the ability of a combined molecular and clinical score to predict the progression of localized prostate cancer. We found that the combined molecular and clinical score predicted progression to metastasis regardless of patient ancestry or treatment. This suggests that the combined molecular and clinical score may be a valuable tool for determining the risk of metastasis in men with newly diagnosed prostate cancer in order to make appropriate treatment decisions.

Characterisation of homologous recombination deficiency in paired primary and recurrent high-grade serous ovarian cancer.

BACKGROUND: Homologous recombination deficiency (HRD) is shown to predict response to DNA-damaging therapies in patients with high-grade serous ovarian cancer (HGSOC); however, changes in HRD during progression remains unknown. METHODS: HRD scores were evaluated in paired primary and/or recurrent HGSOC samples (N = 107) from 54 patients with adjuvant platinum-based chemotherapy. BRCA1/2 mutation, BRCA1 methylation, loss of heterozygosity (LOH), and HRD scores were characterised using tumour DNA-based next-generation sequencing assays. RESULTS: Among 50 evaluable pairs (N = 100 samples), high intra-patient correlation in HRD score was observed (r2 = 0.93). BRCA1/2 mutations, BRCA1/2 LOH, and HRD were maintained between primary and recurrent samples, except for one pair in which a BRCA1 reversion mutation was identified in the recurrent sample. Despite the reversion, both samples were classified as having high HRD scores ( ≥ 42). All samples with BRCA1/2 mutations exhibited high HRD scores; however, high HRD scores were more prevalent than BRCA1/2 mutations (55% vs. 30%, respectively). CONCLUSION: Markers of HRD were maintained between the primary and recurrent samples, regardless of other genomic changes that occurred during recurrence. HRD score/markers in primary tumours may be valuable and adequate for selection of platinum-based therapy and/or poly-ADP-ribose-polymerase (PARP) inhibitors in recurrent HGSOC.

Comparison of cell cycle progression score with two immunohistochemical markers (PTEN and Ki-67) for predicting outcome in prostate cancer after radical prostatectomy.

PURPOSE: Previous studies of the cell cycle progression (CCP) score in surgical specimens of prostate cancer (PCa) in patients treated by radical prostatectomy (RP) demonstrated significant association with time to biochemical recurrence (BCR). In this study, we compared the ability of the CCP score and the expression of PTEN or Ki-67 to predict BCR in a cohort of patients treated by RP. Finally, we constructed the best predictive model for BCR, incorporating biomarkers and relevant clinical variables. MATERIALS AND METHODS: The study population consisted of 652 PCa patients enrolled in a retrospective cohort and who had RP surgery in French urological centers from 2000 to 2007. RESULTS: Among the 652 patients with CCP scores and complete clinical data, BCR events occurred in 41%, and the median time from surgery to the last follow-up among BCR-free patients was 72 months. In univariate Cox analysis, the continuous CCP score and positive Ki-67 predicted recurrence with a HR of 1.44 (95% CI 1.17-1.75; p = 5.3 × 10-4) and 1.89 (95% CI 1.38-2.57; p = 1.6 × 10-4), respectively. In contrast, PTEN expression was not associated with BCR risk. Of the three biomarkers, only the CCP score remained significantly associated in a multivariable Cox model (p = 0.026). The best model incorporated CAPRA-S and CCP scores as predictors, with HRs of 1.32 and 1.24, respectively. CONCLUSION: The CCP score was superior to the two IHC markers (PTEN and Ki-67) for predicting outcome in PCa after RP.

Identification of men with low-risk biopsy-confirmed prostate cancer as candidates for active surveillance.

BACKGROUND: A combined clinical cell-cycle risk (CCR) score that incorporates prognostic molecular and clinical information has been recently developed and validated to improve prostate cancer mortality (PCM) risk stratification over clinical features alone. As clinical features are currently used to select men for active surveillance (AS), we developed and validated a CCR score threshold to improve the identification of men with low-risk disease who are appropriate for AS. METHODS: The score threshold was selected based on the 90th percentile of CCR scores among men who might typically be considered for AS based on NCCN low/favorable-intermediate risk criteria (CCR = 0.8). The threshold was validated using 10-year PCM in an unselected, conservatively managed cohort and in the subset of the same cohort after excluding men with high-risk features. The clinical effect was evaluated in a contemporary clinical cohort. RESULTS: In the unselected validation cohort, men with CCR scores below the threshold had a predicted mean 10-year PCM of 2.7%, and the threshold significantly dichotomized low- and high-risk disease (P = 1.2 × 10-5). After excluding high-risk men from the validation cohort, men with CCR scores below the threshold had a predicted mean 10-year PCM of 2.3%, and the threshold significantly dichotomized low- and high-risk disease (P = 0.020). There were no prostate cancer-specific deaths in men with CCR scores below the threshold in either analysis. The proportion of men in the clinical testing cohort identified as candidates for AS was substantially higher using the threshold (68.8%) compared to clinicopathologic features alone (42.6%), while mean 10-year predicted PCM risks remained essentially identical (1.9% vs. 2.0%, respectively). CONCLUSIONS: The CCR score threshold appropriately dichotomized patients into low- and high-risk groups for 10-year PCM, and may enable more appropriate selection of patients for AS.

Homologous Recombination Deficiency in Patients With Pancreatic Ductal Adenocarcinoma and Response to Chemotherapy.

PURPOSE: Mutations or copy number abnormalities of genes involved in homologous recombination (HR) occur in pancreatic ductal adenocarcinoma (PDAC). DNA-based measures of HR deficiency (HRD) have been developed and may help identify tumors with better response to DNA-damaging agents. This study aimed to describe the HR pathway mutations and HRD status and determine their association with treatment response and outcome in patients with PDAC. PATIENTS AND METHODS: We performed a retrospective analysis of tumor samples from patients treated at Indiana University for locally advanced or metastatic PDAC. Patients were included if they received gemcitabine plus nanoparticle albumin-bound paclitaxel (control) or fluorouracil, oxaliplatin, leucovorin, and irinotecan (FOLFIRINOX) and had adequate follow-up to assess survival and response to therapy. Tumor analysis generated a three-biomarker HRD score and mutation data for 44 genes. RESULTS: Ninety-one samples met inclusion criteria, and 78 samples (formalin-fixed paraffin-embedded, n = 15; fine-needle aspiration, n = 63) generated mutation data. HRD analysis was successful for 57 samples (HRD score: median, 18; range, 5 to 61); the primary cause of failure was low tumor cellularity. Six BRCA1/2 mutations were detected, four with HRD scores in the top decile (P = .011). There was no statistically significant correlation between HRD score and radiographic response (odds ratio per interquartile range, 1.40; P = .32 adjusted for treatment) in either treatment group. In patients treated with FOLFIRINOX, HRD score dichotomized at the median was not associated with progression-free survival (median, 5.3 v 9.4 months for low v high HRD score, respectively; P = .083) or overall survival (median, 11.9 v 10.7 months for low v high HRD score, respectively; P = .76). CONCLUSION: Mutations in DNA repair genes occur in PDAC, and HRD scores can be generated in the majority of patients. The HRD score was not significantly associated with higher response rate or prolonged survival in patients treated with FOLFIRINOX.

Analytical validation of a 12-gene molecular test for the prediction of distant recurrence in breast cancer.

AIM: To validate the analytical performance of a 12-gene molecular assay that predicts distant recurrence for early-stage ER+/HER2- invasive breast cancer as run within a central reference laboratory. MATERIALS & METHODS: Formalin-fixed paraffin-embedded breast resections were evaluated by quantitative reverse transcription polymerase chain reaction for the expression of eight target genes, three housekeeper genes and one control gene to assess for DNA contamination. RESULTS: The assay results were highly correlated with a validated reference laboratory. The assay had a broad linear range for input RNA, with similar amplicon efficiencies for target and housekeeper genes. The assay test was highly reproducible, with comparable inter- and intrabatch precision to the reference laboratory. CONCLUSION: These studies demonstrate that the 12-gene molecular assay is highly robust and accurate.

Prognostic utility of biopsy-derived cell cycle progression score in patients with National Comprehensive Cancer Network low-risk prostate cancer undergoing radical prostatectomy: implications for treatment guidance.

OBJECTIVES: To determine the prognostic utility of the cell cycle progression (CCP) score in men with National Comprehensive Cancer Network (NCCN)-defined low-risk prostate cancer (PCa) undergoing radical prostatectomy (RP). PATIENTS AND METHODS: Men who underwent RP for Gleason score ≤6 PCa at three institutions (Martini Clinic [MC], Durham Veterans Affairs Medical Center [DVA] and Intermountain Healthcare [IH]) were identified. The CCP score was obtained from diagnostic (DVA, IH) or simulated biopsies (MC). The primary outcome was biochemical recurrence (BCR; prostate-specific antigen ≥0.2 ng/mL) after RP. The prognostic utility of the CCP score was assessed using Kaplan-Meier analysis and multivariable Cox proportional hazards models in the subset of men meeting NCCN low-risk criteria and in the overall cohort. RESULTS: Among the 236 men identified, 80% (188/236) met the NCCN low-risk criteria. Five-year BCR-free survival for the low (<0), intermediate (0-1) and high (>1) CCP score groups was 89.2%, 80.4%, 64.7%, respectively, in the low-risk cohort (P = 0.03), and 85.9%, 79.1%, 63.1%, respectively, in the overall cohort (P = 0.041). In multivariable models adjusting for clinical and pathological variables with the Cancer of the Prostate Risk Assessment (CAPRA) score, the CCP score was an independent predictor of BCR in the low-risk (hazard ratio [HR] 1.77 per unit score, 95% confidence interval [CI] 1.21, 2.58; P = 0.003) and overall cohorts (HR 1.41 per unit score, 95% CI 1.02, 1.96; P = 0.039). CONCLUSION: In a cohort of men with NCCN-defined low-risk PCa, the CCP score improved clinical risk stratification of men who were at increased risk of BCR, which suggests the CCP score could improve the assessment of candidacy for active surveillance and guide optimum treatment selection in these patients with otherwise similar clinical characteristics.

Patterns of retinal hemorrhage associated with pediatric cerebral sinovenous thrombosis.

BACKGROUND: Cerebral sinovenous thrombosis (CSVT) has been proposed as an alternative cause of retinal hemorrhage (RH) in children being evaluated for abusive head trauma. This study investigated the prevalence and characteristics of RH in children with CSVT. METHODS: The medical records of children >6 weeks of age with newly diagnosed CSVT and fundus examination by an ophthalmologist were examined retrospectively. Primary outcomes were presence and patterns of RH. RESULTS: A total of 29 children (median age, 9 years; range, 7 weeks to 17 years) were studied. Of these, 5 (17%) had RH, in 4 of whom RH were peripapillary, superficial, intraretinal, and adjacent to a swollen optic disk. In the fifth child, who had meningitis, sepsis, and multiple cerebral infarcts, there were a moderate number of posterior pole intraretinal hemorrhages. Eighteen children (62%) had optic disk swelling. In 13 children, cerebrospinal fluid opening pressure was recorded (range, 27-59 cm H2O). CSVT risk factors included meningitis, mastoiditis, and hypercoagulability. CONCLUSIONS: RH in pediatric CSVT was uncommon. When RHs were present, the appearance matched RH patterns known to be caused by medical conditions, such as raised intracranial pressure and sepsis, also present in these children. These findings suggest that the RHs are due to these other causes and not directly to CSVT itself. In children with CSVT, if RHs are multilayered, extend beyond the peripapillary region into the rest of the posterior pole or retinal periphery, or occur in the absence of optic disk swelling, another etiology for the RH should be sought.

Intratumor Heterogeneity of Homologous Recombination Deficiency in Primary Breast Cancer.

Purpose: The 3-biomarker homologous recombination deficiency (HRD) assay measures the number of telomeric allelic imbalances, loss of heterozygosity, and large-scale state transitions in tumor DNA and combines these metrics into a single score that reflects DNA repair deficiency. The goal of this study is to assess the consistency of these HRD measures in different biopsies from distinct areas of the same cancer.Experimental Design: HRD scores, BRCA mutation status, and BRCA1 promoter methylation were assessed in 99 samples from 33 surgically resected, stage I-III breast cancers; each cancer was biopsied in three distinct areas. Homologous recombination repair (HR) deficiency was defined as either high HRD score (≥42) or tumor BRCA mutation.Results: Eighty-one biopsies from 32 cancers were analyzed. Tumor BRCA status was available for all samples, HRD scores for 70, and BRCA1 methylation values for 76 samples. The BRCA1/2 mutation and promoter methylation status and HR category showed perfect concordance across all biopsies from the same cancer. All tumors with BRCA1/2 mutations or promoter methylation had high HRD scores, as did 17% (4/24) of the BRCA1/2 wild-type and nonmethylated tumors. The HRD scores were also highly consistent between different biopsies from the same tumor with an intraclass correlation coefficient of 0.977, indicating that only 2.3% of the variance is attributed to within-tumor biopsy-to-biopsy variation.Conclusions: These results indicate that within-tumor spatial heterogeneity for HRD metrics and the technical noise in the assay are small and do not influence HRD scores and HR status. Clin Cancer Res; 23(5); 1193-9. ©2016 AACR.

Sixth Nerve Palsy in Paediatric Intracranial Hypertension.

The purpose of this study was to report the incidence and describe the characteristics of sixth cranial nerve (CN VI) palsy in paediatric patients with intracranial hypertension (IH). A retrospective chart review of central Ohio children diagnosed with IH over the 3-year period from 2010 to 2013 was conducted. IH without identifiable cause was defined as idiopathic intracranial hypertension (IIH), whereas IH with identifiable pathologic aetiology was deemed secondary intracranial hypertension (SIH). A subset of patients with CN VI palsy was identified. Data collected included patient age, gender, past medical history, aetiology of SIH, ophthalmic examination, lumbar puncture results, neuroimaging results, and response to treatment. Seventy-eight children with intracranial hypertension were included in the study. Nine (11.5%) children (four males, five females; median age 14, range: 3-18) were found to have a unilateral (n = 2) or bilateral (n = 7) CN VI palsy. Five children had IIH; the remaining four had SIH from cerebral venous sinus thrombosis (n = 2) and infection (n = 2). The mean lumbar puncture opening pressure for the nine patients with CN VI palsy was 40 cm H2O (range: 21-65 cm H2O). Papilloedema was present in 8/9 (89%) patients. One patient required a lumboperitoneal shunt, and two others required optic nerve sheath fenestrations in addition to medical management. All cases of CN VI palsy resolved with treatment. In our primary service area, the incidence of CN VI palsy is approximately 12% among paediatric IH patients. The majority of cases with CN VI palsy presented with papilloedema and all cases resolved with treatment of intracranial hypertension.

Use of the cell cycle progression (CCP) score for predicting systemic disease and response to radiation of biochemical recurrence.

BACKGROUND: Determining the optimal treatment for biochemical recurrence (BCR) after radical prostatectomy (RP) is challenging. OBJECTIVE: We evaluated the ability of CCP score (a prognostic RNA expression signature) to discriminate between systemic disease and local recurrence in patients with BCR after RP. METHODS: Sixty patients with BCR after RP were selected for analysis based on: 1) metastatic disease, 2) non-response to salvage external beam radiotherapy (EBRT), and 3) durable response to salvage EBRT. CCP scores were generated from the RNA expression of 46 genes. Logistic regression assessed the association between CCP score and patient group. RESULTS: Passing CCP scores were generated for 47 patients with complete clinical and pathologic data. CCP score predicted clinical status when comparing patients with metastatic disease or non-responders to salvage therapy to patients with durable response (p = 0.006). CCP score remained significantly predictive of clinical status after accounting for time to BCR, PSA level at BCR, and Gleason score (p = 0.0031). CONCLUSIONS: Elevated CCP score was associated with increased risk of systemic disease, indicating that CCP score may be useful in identifying patients with BCR who are most likely to benefit from salvage radiation therapy.

Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer.

PURPOSE: BRCA1/2-mutated and some sporadic triple-negative breast cancers (TNBC) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed on the basis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). EXPERIMENTAL DESIGN: We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score ≥42 or BRCA1/2 mutation, with response to platinum-based therapy. RESULTS: In a trial of neoadjuvant platinum, gemcitabine, and iniparib, HR deficiency predicted residual cancer burden score of 0 or I (RCB 0/I) and pathologic complete response (pCR; OR = 4.96, P = 0.0036; OR = 6.52, P = 0.0058). HR deficiency remained a significant predictor of RCB 0/I when adjusted for clinical variables (OR = 5.86, P = 0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/I and pCR (OR = 10.18, P = 0.0011; OR = 17.00, P = 0.0066). In a multivariable model of RCB 0/I, HR deficiency retained significance when clinical variables were included (OR = 12.08, P = 0.0017). When restricted to BRCA1/2 nonmutated tumors, response was higher in patients with high HRD scores: RCB 0/I P = 0.062, pCR P = 0.063 in the neoadjuvant platinum, gemcitabine, and iniparib trial; RCB 0/I P = 0.0039, pCR P = 0.018 in the neoadjuvant cisplatin trials. CONCLUSIONS: HR deficiency identifies TNBC tumors, including BRCA1/2 nonmutated tumors more likely to respond to platinum-containing therapy. Clin Cancer Res; 22(15); 3764-73. ©2016 AACR.