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

Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts

Objectives In older patients, the the D-dimer test for pulmonary embolism has reduced specificity and is therefore less useful. In this study a new, age dependent cut-off value for the test was devised and its usefulness with older patients assessed

Excluding pulmonary embolism in primary care using the Wells-rule in combination with a point-of care D-dimer test: a scenario analysis

ABSTRACT: BACKGROUND: In secondary care the Wells clinical decision rule (CDR) combined with a quantitative D-dimer test can exclude pulmonary embolism (PE) safely. The introduction of point-of-care (POC) D-dimer tests facilitates a similar diagnostic strategy in primary care. We estimated failure-rate and efficiency of a diagnostic strategy using the Wells-CDR combined with a POC-D-dimer test for excluding PE in primary care. We considered ruling out PE safe if the failure rate was <2% with a maximum upper confidence limit of 2.7%. METHODS: We performed a scenario-analysis on data of 2701 outpatients suspected of PE. We used test characteristics of two qualitative POC-D-dimer tests, as derived from a meta-analysis and combined these with the Wells-CDR-score. RESULTS: In scenario 1 (SimpliRed-D-dimer sensitivity 85%, specificity 74%) PE was excluded safely in 23.8% of patients but only by lowering the cut-off value of the Wells rule to <2. (failure rate: 1.4%, 95% CI 0.6-2.6%) In scenario 2 (Simplify-D-dimer sensitivity 87%, specificity 62%) PE was excluded safely in 12.4% of patients provided that the Wells-cut-off value was set at 0. (failure rate: 0.9%, 95% CI 0.2-2.6%) CONCLUSION: Theoretically a diagnostic strategy using the Wells-CDR combined with a qualitative POC-D-dimer test can be used safely to exclude PE in primary care albeit with only moderate efficienc

Validity and clinical utility of the simplified Wells rule for assessing clinical probability for the exclusion of pulmonary embolism.

International audienceThe recently introduced simplified Wells rule for the exclusion of pulmonary embolism (PE) assigns only one point to the seven variables of the original Wells rule. This study was performed to independently validate the simplified Wells rule for the exclusion of PE. We retrospectively calculated the prevalence of PE in the "unlikely" probability categories of the original Wells (cut-off < or =4) and the simplified Wells rule (cut-off < or =1) in 922 consecutive patients with clinically suspected PE from a multicenter cohort study. We compared the three-month incidence of venous thromboembolism (VTE) in patients with an unlikely probability and a normal D-dimer test using both scores, and the proportion of patients with this combination (clinical utility). The proportion of patients categorized as PE "unlikely" was similar using the original (78%) and the simplified (70%) Wells rule. The prevalence of PE was 13% (95% confidence interval [CI], 11-16%) and 12% (95%CI, 9.7-15%) for the original Wells and simplified Wells "unlikely" categories, respectively. None of the patients with PE "unlikely" and a normal D-dimer test experienced VTE during three-month follow-up. The proportions of patients in whom further tests could safely be withheld based on PE "unlikely" and a normal D-dimer test was 28% (95%CI, 25-31%) using the original and 26% (95%CI, 24-29%) using the simplified Wells rule. In this external retrospective validation study, the simplified Wells rule appeared to be safe and clinically useful, although prospective validation remains necessary. Simplification of the Wells rule may enhance the applicability

Cuba : les temporalités et tensions du changement

Depuis l'arrivée au pouvoir de Raúl Castro en 2008, la reprise des relations diplomatiques avec les États-Unis en 2014, et, surtout, depuis la mort de Fidel Castro en novembre 2016, les discours académiques et politiques sur la transition cubaine se multiplient. Face aux signes d’épuisement des structures cubaines verrouillées par un régime inflexible (appauvrissement de la population, faillite de l’économie, émigration, violations continuelles des droits de l’homme), certains économistes proclament que la transition cubaine est devenue inéluctable, bien au-delà des timides réformes esquissées par le régime. D’autres voix s’élèvent, cependant, en faveur de l’aménagement d’une voie socialiste viable, nourrie de l’ouverture internationale, susceptible de relancer la croissance économique et d’améliorer le bien-être de la population. Les débats montrent que la vigueur de la guerre froide perdure et que certains événements semblant constituer des « tournants » dans l'histoire cubaine n'ont en réalité d'effets que sur de longues périodes

Performance of the McGill Interactive Pediatric OncoGenetic Guidelines for Identifying Cancer Predisposition Syndromes.

Importance Prompt recognition of a child with a cancer predisposition syndrome (CPS) has implications for cancer management, surveillance, genetic counseling, and cascade testing of relatives. Diagnosis of CPS requires practitioner expertise, access to genetic testing, and test result interpretation. This diagnostic process is not accessible in all institutions worldwide, leading to missed CPS diagnoses. Advances in electronic health technology can facilitate CPS risk assessment. Objective To evaluate the diagnostic accuracy of a CPS prediction tool (McGill Interactive Pediatric OncoGenetic Guidelines [MIPOGG]) in identifying children with cancer who have a low or high likelihood of having a CPS. Design, Setting, and Participants In this international, multicenter diagnostic accuracy study, 1071 pediatric (<19 years of age) oncology patients who had a confirmed CPS (12 oncology referral centers) or who underwent germline DNA sequencing through precision medicine programs (6 centers) from January 1, 2000, to July 31, 2020, were studied. Exposures Exposures were MIPOGG application in patients with cancer and a confirmed CPS (diagnosed through routine clinical care; n = 413) in phase 1 and MIPOGG application in patients with cancer who underwent germline DNA sequencing (n = 658) in phase 2. Study phases did not overlap. Data analysts were blinded to genetic test results. Main Outcomes and Measures The performance of MIPOGG in CPS recognition was compared with that of routine clinical care, including identifying a CPS earlier than practitioners. The tool's test characteristics were calculated using next-generation germline DNA sequencing as the comparator. Results In phase 1, a total of 413 patients with cancer (median age, 3.0 years; range, 0-18 years) and a confirmed CPS were identified. MIPOGG correctly recognized 410 of 412 patients (99.5%) as requiring referral for CPS evaluation at the time of primary cancer diagnosis. Nine patients diagnosed with a CPS by a practitioner after their second malignant tumor were detected by MIPOGG using information available at the time of the first cancer. In phase 2, of 658 children with cancer (median age, 6.6 years; range, 0-18.8 years) who underwent comprehensive germline DNA sequencing, 636 had sufficient information for MIPOGG application. When compared with germline DNA sequencing for CPS detection, the MIPOGG test characteristics for pediatric-onset CPSs were as follows: sensitivity, 90.7%; specificity, 60.5%; positive predictive value, 17.6%; and negative predictive value, 98.6%. Tumor DNA sequencing data confirmed the MIPOGG recommendation for CPS evaluation in 20 of 22 patients with established cancer-CPS associations. Conclusions and Relevance In this diagnostic study, MIPOGG exhibited a favorable accuracy profile for CPS screening and reduced time to CPS recognition. These findings suggest that MIPOGG implementation could standardize and rationalize recommendations for CPS evaluation in children with cancer