Molecular analysis distinguishes metastatic disease from second cancers in patients with retinoblastoma

The pediatric ocular tumor retinoblastoma readily metastasizes, but these lesions can masquerade as histologically similar pediatric small round blue cell tumors. Since 98% of retinoblastomas have RB1 mutations and a characteristic genomic copy number “signature”, genetic analysis is an appealing adjunct to histopathology to distinguish retinoblastoma metastasis from second primary cancer in retinoblastoma patients. Here, we describe such an approach in two retinoblastoma cases. In patient one, allele-specific (AS)-PCR for a somatic nonsense mutation confirmed that a temple mass was metastatic retinoblastoma. In a second patient, a rib mass shared somatic copy number gains and losses with the primary tumor. For definitive diagnosis, however, an RB1 mutation was needed, but heterozygous promoter→exon 11 deletion was the only RB1 mutation detected in the primary tumor. We used a novel application of inverse PCR to identify the deletion breakpoint. Subsequently, AS-PCR designed for the breakpoint confirmed that the rib mass was metastatic retinoblastoma. These cases demonstrate that personalized molecular testing can confirm retinoblastoma metastases and rule out a second primary cancer, thereby helping to direct the clinical management

Optimizing huddle engagement through leadership and problem-solving within primary care: A study protocol for a cluster randomized trial

Abstract Background Team-based care has been identified as a key component in transforming primary care. An important factor in implementing team-based care is the requirement for teams to have daily huddles. During huddles, the care team, comprising physicians, nurses, and administrative staff, come together to discuss their daily schedules, track problems, and develop countermeasures to fix these problems. However, the impact of these huddles on staff burnout over time and patient outcomes are not clear. Further, there are challenges to implementing huddles in fast-paced primary care clinics. We will test whether the impact of a behavioral intervention of leadership training and problem-solving during the daily huddling process will result in higher consistent huddling in the intervention arm and result in higher team morale, reduced burnout, and improved patient outcomes. Methods/design We will conduct a care-team-level cluster randomized trial within primary care practices in two Midwestern states. The intervention will comprise a 1-day training retreat for leaders of primary care teams, biweekly sessions between huddle optimization coaches and members of the primary care teams, as well as coaching site visits at 30 and 100 days post intervention. This behavioral intervention will be compared to standard care, in which care teams have huddles without any support or training. Surveys of primary care team members will be administered at baseline (prior to training), 100 days (for the intervention arm only), and 180 days to assess team dynamics. The primary outcome of this trial will be team morale. Secondary outcomes will assess the impact of this intervention on clinician burnout, patient satisfaction, and quality of care. Discussion This trial will provide evidence on the impact of a behavioral intervention to implement huddles as a key component of team-based care models. Knowledge gained from this trial will be critical to broader deployment and successful implementation of team-based care models. Trial registration Clinicaltrials.gov , NCT03062670 . Registered on 23 February 2017

Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies

SummaryBackgroundRetinoblastoma is the childhood retinal cancer that defined tumour-suppressor genes. Previous work shows that mutation of both alleles of the RB1 retinoblastoma suppressor gene initiates disease. We aimed to characterise non-familial retinoblastoma tumours with no detectable RB1 mutations.MethodsOf 1068 unilateral non-familial retinoblastoma tumours, we compared those with no evidence of RB1 mutations (RB1+/+) with tumours carrying a mutation in both alleles (RB1−/−). We analysed genomic copy number, RB1 gene expression and protein function, retinal gene expression, histological features, and clinical data.FindingsNo RB1 mutations (RB1+/+) were reported in 29 (2·7%) of 1068 unilateral retinoblastoma tumours. 15 of the 29 RB1+/+ tumours had high-level MYCN oncogene amplification (28–121 copies; RB1+/+MYCNA), whereas none of 93 RB1−/− primary tumours tested showed MYCN amplification (p<0·0001). RB1+/+MYCNA tumours expressed functional RB1 protein, had fewer overall genomic copy-number changes in genes characteristic of retinoblastoma than did RB1−/− tumours, and showed distinct aggressive histological features. MYCN amplification was the sole copy-number change in one RB1+/+MYCNA retinoblastoma. One additional MYCNA tumour was discovered after the initial frequencies were determined, and this is included in further analyses. Median age at diagnosis of the 17 children with RB1+/+MYCNA tumours was 4·5 months (IQR 3·5–10), compared with 24 months (15–37) for 79 children with non-familial unilateral RB1−/− retinoblastoma.InterpretationAmplification of the MYCN oncogene might initiate retinoblastoma in the presence of non-mutated RB1 genes. These unilateral RB1+/+MYCNA retinoblastomas are characterised by distinct histological features, only a few of the genomic copy-number changes that are characteristic of retinoblastoma, and very early age of diagnosis.FundingNational Cancer Institute–National Institutes of Health, Canadian Institutes of Health Research, German Research Foundation, Canadian Retinoblastoma Society, Hyland Foundation, Toronto Netralaya and Doctors Lions Clubs, Ontario Ministry of Health and Long Term Care, UK-Essen, and Foundations Avanti-STR and KiKa

Optimizing huddle engagement through leadership and problem-solving within primary care: A study protocol for a cluster randomized trial

Abstract Background Team-based care has been identified as a key component in transforming primary care. An important factor in implementing team-based care is the requirement for teams to have daily huddles. During huddles, the care team, comprising physicians, nurses, and administrative staff, come together to discuss their daily schedules, track problems, and develop countermeasures to fix these problems. However, the impact of these huddles on staff burnout over time and patient outcomes are not clear. Further, there are challenges to implementing huddles in fast-paced primary care clinics. We will test whether the impact of a behavioral intervention of leadership training and problem-solving during the daily huddling process will result in higher consistent huddling in the intervention arm and result in higher team morale, reduced burnout, and improved patient outcomes. Methods/design We will conduct a care-team-level cluster randomized trial within primary care practices in two Midwestern states. The intervention will comprise a 1-day training retreat for leaders of primary care teams, biweekly sessions between huddle optimization coaches and members of the primary care teams, as well as coaching site visits at 30 and 100 days post intervention. This behavioral intervention will be compared to standard care, in which care teams have huddles without any support or training. Surveys of primary care team members will be administered at baseline (prior to training), 100 days (for the intervention arm only), and 180 days to assess team dynamics. The primary outcome of this trial will be team morale. Secondary outcomes will assess the impact of this intervention on clinician burnout, patient satisfaction, and quality of care. Discussion This trial will provide evidence on the impact of a behavioral intervention to implement huddles as a key component of team-based care models. Knowledge gained from this trial will be critical to broader deployment and successful implementation of team-based care models. Trial registration Clinicaltrials.gov, NCT03062670. Registered on 23 February 2017