The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co‐segregation, family cancer history profile, co‐occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case‐control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene‐specific calibration of evidence types used for variant classification.

Adult neural progenitor cells (NPC) are an attractive source for cell transplantation and neural tissue replacement after central nervous system (CNS) injury. Following transplantation of NPC cell suspensions into the acutely injured rat spinal cord, NPC survive; however, they migrate away from the lesion site and are unable to replace the injury-induced lesion cavity. In the present study we examined (i) whether NPC can be retained within the lesion site after co-transplantation with primary fibroblasts, and (ii) whether NPC promote axonal regeneration following spinal cord injury. Co-cultivation of NPC with fibroblasts demonstrated that NPC adhere to fibroblasts and the extracellular matrix produced by fibroblasts. In the presence of fibroblasts, the differentiation pattern of co-cultivated NPC was shifted towards glial differentiation. Three weeks after transplantation of adult spinal-cord-derived NPC with primary fibroblasts as mixed cell suspensions into the acutely injured cervical spinal cord in adult rats, the lesion cavity was completely replaced. NPC survived throughout the graft and differentiated exclusively into glial cells. Quantification of neurofilament-labeled axons and anterogradely labeled corticospinal axons indicated that NPC co-grafted with fibroblasts significantly enhanced axonal regeneration. Both neurofilament-labeled axons and corticospinal axons aligned longitudinally along GFAP-expressing NPC-derived cells, which displayed a bipolar morphology reminiscent of immature astroglia. Thus, grafted astroglial differentiated NPC promote axon regrowth following spinal cord injury by means of cellular guidance.

BACKGROUND Survival after first‐line therapy is poor for patients with glioblastoma. The role of second‐line treatment for recurrent disease is controversial. The authors studied the outcome in a subset of patients with glioblastoma who were selected for an aggressive reintervention strategy at the time of progression. Their objectives were to improve patients' overall survival with sustained quality of life and to make comparisons with overall survival in unselected patients. METHODS Overall, 168 patients were eligible for retrospective analysis. Ninety patients received specific therapy for disease recurrence (reintervention group) by specific criteria. RESULTS In the reintervention group, promising median overall survival (mOS) results after diagnosis (61.5 weeks) and progression (33 weeks) were obtained. The progression‐free survival (PFS) rate at 12 months and the overall survival rate were superior in the reintervention group (71% at 12 months and 32% at 24 months) compared with the total cohort (45% and 20%, respectively) and the standard group (15% and 5%, respectively). A matched‐pair analysis (n = 46 in each group), with an mOS period of 65.5 versus 28.5 weeks, confirmed these data. Quality of life was stable or slightly improved during reinterventions in a subset of patients treated within clinical studies. CONCLUSIONS The majority of patients in the current series were treated with a reintervention strategy, which had an impact on PFS and mOS. A second resection, focal radiotherapy (in selected cases), and additional chemotherapeutic regimens should be considered for patients with recurrent glioblastoma. Cancer 2003;98:2678–86. © 2003 American Cancer Society.