GENESIS: a French national resource to study the missing heritability of breast cancer.

BACKGROUND: Less than 20% of familial breast cancer patients who undergo genetic testing for BRCA1 and BRCA2 carry a pathogenic mutation in one of these two genes. The GENESIS (GENE SISter) study was designed to identify new breast cancer susceptibility genes in women attending cancer genetics clinics and with no BRCA1/2 mutation. METHODS: The study involved the French national network of family cancer clinics. It was based on enrichment in genetic factors of the recruited population through case selection relying on familial criteria, but also on the consideration of environmental factors and endophenotypes like mammary density or tumor characteristics to assess potential genetic heterogeneity. One of the initial aims of GENESIS was to recruit affected sibpairs. Siblings were eligible when index cases and at least one affected sister were diagnosed with infiltrating mammary or ductal adenocarcinoma, with no BRCA1/2 mutation. In addition, unrelated controls and unaffected sisters were recruited. The enrolment of patients, their relatives and their controls, the collection of the clinical, epidemiological, familial and biological data were centralized by a coordinating center. RESULTS: Inclusion of participants started in February 2007 and ended in December 2013. A total of 1721 index cases, 826 affected sisters, 599 unaffected sisters and 1419 controls were included. 98% of participants completed the epidemiological questionnaire, 97% provided a blood sample, and 76% were able to provide mammograms. Index cases were on average 59 years old at inclusion, were born in 1950, and were 49.7 years of age at breast cancer diagnosis. The mean age at diagnosis of affected sisters was slightly higher (51.4 years). The representativeness of the control group was verified. CONCLUSIONS: The size of the study, the availability of biological specimens and the clinical data collection together with the detailed and complete epidemiological questionnaire make this a unique national resource for investigation of the missing heritability of breast cancer, by taking into account environmental and life style factors and stratifying data on endophenotypes to decrease genetic heterogeneity.

Delirium Assessment Tools for Use in Critically Ill Adults: A Psychometric Analysis and Systematic Review.

BACKGROUND: Delirium is highly prevalent in critically ill patients. Its detection with valid tools is crucial. OBJECTIVE: To analyze the development and psychometric properties of delirium assessment tools for critically ill adults. METHODS: Databases were searched to identify relevant studies. Inclusion criteria were English language, publication before January 2015, 30 or more patients, and patient population of critically ill adults (>18 years old). Search terms were delirium, scales, critically ill patients, adult, validity, and reliability. Thirty-six manuscripts were identified, encompassing 5 delirium assessment tools (Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), Cognitive Test for Delirium, Delirium Detection Score, Intensive Care Delirium Screening Checklist (ICDSC), and Nursing Delirium Screening Scale). Two independent reviewers analyzed the psychometric properties of these tools by using a standardized scoring system (range, 0-20) to assess the tool development process, reliability, validity, feasibility, and implementation of each tool. RESULTS: Psychometric properties were very good for the CAM-ICU (19.6) and the ICDSC (19.2), moderate for the Nursing Delirium Screening Scale (13.6), low for the Delirium Detection Score (11.2), and very low for the Cognitive Test for Delirium (8.2). CONCLUSIONS: The results indicate that the CAM-ICU and the ICDSC are the most valid and reliable delirium assessment tools for critically ill adults. Additional studies are needed to further validate these tools in critically ill patients with neurological disorders and those at various levels of sedation or consciousness.

Examining Factors That Impact Inpatient Management of Diabetes and the Role of Insulin Pen Devices.

Insulin administration in the acute care setting is an integral component of inpatient diabetes management. Although some institutions have moved to insulin pen devices, many acute care settings continue to employ the vial and syringe method of insulin administration. The aim of this study was to evaluate the impact of insulin pen implementation in the acute care setting on patients, healthcare workers and health resource utilization. A review of published literature, including guidelines, was conducted to identify how insulin pen devices in the acute care setting may impact inpatient diabetes management. Previously published studies have revealed that insulin pen devices have the potential to improve inpatient management through better glycemic control, increased adherence and improved self-management education. Furthermore, insulin pen devices may result in cost savings and improved safety for healthcare workers. There are benefits to the use of insulin pen devices in acute care and, as such, their implementation should be considered.

Significant contribution of large BRCA1 gene rearrangements in 120 French breast and ovarian cancer families.

Genetic linkage data have shown that alterations of the BRCA1 gene are responsible for the majority of hereditary breast-ovarian cancers. However, BRCA1 germline mutations are found much less frequently than expected, especially as standard PCR-based mutation detection approaches focus on point and small gene alterations. In order to estimate the contribution of large gene rearrangements to the BRCA1 mutation spectrum, we have extensively analysed a series of 120 French breast-ovarian cancer cases. Thirty-eight were previously found carrier of a BRCA1 point mutation, 14 of a BRCA2 point mutation and one case has previously been reported as carrier of a large BRCA1 deletion. The remaining 67 cases were studied using the BRCA1 bar code approach on combed DNA which allows a panoramic view of the BRCA1 region. Three additional rearrangements were detected: a recurrent 23.8 kb deletion of exons 8-13, a 17.2 kb duplication of exons 3-8 and a 8.6 kb duplication of exons 18-20. Thus, in our series, BRCA1 large rearrangements accounted for 3.3% (4/120) of breast-ovarian cancer cases and 9.5% (4/42) of the BRCA1 gene mutation spectrum, suggesting that their screening is an important step that should be now systematically included in genetic testing surveys.

Hypocalcemia following pamidronate administration for bone metastases of solid tumor: three clinical case reports.

Bisphosphonates, such as pamidronate, are a new class of drugs, initially described for treatment of neoplasic hypercalcemia. Currently, they also may be used in the treatment of bone metastases from solid tumor, even without hypercalcemia. Hypocalcemia is a potential adverse effect of these drugs, which is considered infrequent and rarely symptomatic. We describe three cases of severe hypocalcemia following one injection of pamidronate. The three patients had bone metastases from solid tumors (breast in two cases, prostate in one), at least partially osteoblastic, and none had hypercalcemia. The induced hypocalcemia was rapid in onset, severe, and durable. The mechanism seems to be multiple and may include both the expected reduction of osteolysis and also a rapid and direct action on parathyroid glands followed by resistance to parathormone. Some elements could amplify the phenomenon, such as latent hypoparathyroidism after surgery, cervical radiotherapy, hypomagnesemia, or low 25 hydroxy vitamin D (25OH D). For patients who have such risk factors, it may be useful to check calcium several days after the first injection.