Benjamin S. Wilfond

Bio: Benjamin S. Wilfond is an academic researcher from University of Washington. The author has contributed to research in topics: Informed consent & Medicine. The author has an hindex of 54, co-authored 295 publications receiving 14133 citations. Previous affiliations of Benjamin S. Wilfond include Johns Hopkins University & Seattle Children's.

Gene-Expression Profiles in Hereditary Breast Cancer

Abstract: Background Many cases of hereditary breast cancer are due to mutations in either the BRCA1 or the BRCA2 gene. The histopathological changes in these cancers are often characteristic of the mutant gene. We hypothesized that the genes expressed by these two types of tumors are also distinctive, perhaps allowing us to identify cases of hereditary breast cancer on the basis of gene-expression profiles. Methods RNA from samples of primary tumors from seven carriers of the BRCA1 mutation, seven carriers of the BRCA2 mutation, and seven patients with sporadic cases of breast cancer was compared with a microarray of 6512 complementary DNA clones of 5361 genes. Statistical analyses were used to identify a set of genes that could distinguish the BRCA1 genotype from the BRCA2 genotype. Results Permutation analysis of multivariate classification functions established that the gene-expression profiles of tumors with BRCA1 mutations, tumors with BRCA2 mutations, and sporadic tumors differed significantly from each othe...

Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents

Abstract: In 1995, the American Society of Human Genetics (ASHG) and American College of Medical Genetics and Genomics (ACMG) jointly published a statement on genetic testing in children and adolescents. In the past 20 years, much has changed in the field of genetics, including the development of powerful new technologies, new data from genetic research on children and adolescents, and substantial clinical experience. This statement represents current opinion by the ASHG on the ethical, legal, and social issues concerning genetic testing in children. These recommendations are relevant to families, clinicians, and investigators. After a brief review of the 1995 statement and major changes in genetic technologies in recent years, this statement offers points to consider on a broad range of test technologies and their applications in clinical medicine and research. Recommendations are also made for record and communication issues in this domain and for professional education.

Managing incidental findings in human subjects research: Analysis and recommendations

Abstract: Researchers, institutional review boards (IRBs), participants in human subjects research, and their families face an important but largely neglected problem — how should incidental findings (IFs) be managed in human subjects research. If researchers unexpectedly stumble upon information of potential health or reproductive significance, should they seek expert evaluation, contact the participant’s physician, tell the research participant, or respond with some combination? What should consent forms and the entire consent process say about how IFs will be handled in research? What should IRBs require?

An Official American Thoracic Society Clinical Policy Statement: Palliative Care for Patients with Respiratory Diseases and Critical Illnesses

Abstract: Executive Summary Introduction Methods Goals, Timing, and Settings for Palliative Care Decision-making Process Advance Directives Care Planning and Delivery Hospice Care Alternative End-of-Life Decisions Symptom Management Dyspnea Management Pain Management Management of Psychological and Spiritual Distress and Suffering Withdrawal of Mechanical Ventilation Process of Decision Making Process of Withdrawing Mechanical Ventilation Bereavement Care Barriers to Palliative Care Program Development, Education, Training, and Research in Palliative Care

Palliative care for children

Abstract: This statement presents an integrated model for providing palliative care for children living with a life-threatening or terminal condition. Advice on the development of a palliative care plan and on working with parents and children is also provided. Barriers to the provision of effective pediatric palliative care and potential solutions are identified. The American Academy of Pediatrics recommends the development and broad availability of pediatric palliative care services based on child-specific guidelines and standards. Such services will require widely distributed and effective palliative care education of pediatric health care professionals. The Academy offers guidance on responding to requests for hastening death, but does not support the practice of physician-assisted suicide or euthanasia for children. ABBREVIATION. AAP, American Academy of Pediatrics. In modern society, we expect children to outlive their parents. However, 53 000 children in the United States die every year from trauma, lethal congenital conditions, extreme prematurity, heritable disorders, or acquired illness.1 The causes of death in children are substantially different from the causes of death in adults; thus, palliative care guidelines that are appropriate for adults are often inappropriate for children. For children living with lifethreatening or terminal conditions, medical professionals are obligated to ensure that medical technology is used only when the benefits for the child outweigh the burdens. An infant or child will benefit from palliative care when no treatment has been shown to alter substantially the expected progression toward death. Palliative care seeks to enhance quality of life in the face of an ultimately terminal condition. Palliative treatments focus on the relief of symptoms (eg, pain, dyspnea) and conditions (eg, loneliness) that cause distress and detract from the child’s enjoyment of life. It also seeks to ensure that bereaved families are able to remain functional and intact. Hospice care refers to a package of palliative care services (including, for example, durable medical equipment, and both diagnostic and therapeutic interventions), generally provided at a limited per diem rate by a multidisciplinary group of physicians, nurses, and other personnel, such as chaplains, health aides, and bereavement counselors. Palliative care includes the control of pain and other symptoms and addresses the psychological, social, or spiritual problems of children (and their families) living with life-threatening or terminal conditions.2,3 The goal of palliative care is the achievement of the best quality of life for patients and their families, consistent with their values, regardless of the location of the patient.4 The American Academy of Pediatrics (AAP) has previously addressed the limitation or withdrawal of life-sustaining medical treatment.5–7 Specific strategies for palliative management of pain, dyspnea, agitation, nausea, vomiting, seizures, depression, anxiety, grief, and other symptoms can be found in other sources.8–11 PRINCIPLES FOR PALLIATIVE CARE The AAP calls for the development of clinical policies and minimum standards that promote the welfare of infants and children living with life-threatening or terminal conditions and their families, with the goal of providing equitable and effective support for curative, life-prolonging, and palliative care.12 The following principles serve as the foundation for an integrated model of palliative care. Respect for the Dignity of Patients and Families The provision of palliative care for children includes sensitivity to and respect for the child’s and family’s wishes. In consultation with the child’s parent or guardian, the plan of care incorporates respect for the terminally ill child’s preferences concerning testing, monitoring, and treatment. Consistent with this principle of respect, information about palliative care should be readily available and parents may choose to initiate a referral to a pediatric palliative care program. The needs of families must be attended to both during the illness and after the child’s death to improve their ability to survive the ordeal intact. Access to Competent and Compassionate Palliative

Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications

Abstract: The purpose of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome. A total of 85 cDNA microarray experiments representing 78 cancers, three fibroadenomas, and four normal breast tissues were analyzed by hierarchical clustering. As reported previously, the cancers could be classified into a basal epithelial-like group, an ERBB2-overexpressing group and a normal breast-like group based on variations in gene expression. A novel finding was that the previously characterized luminal epithelial/estrogen receptor-positive group could be divided into at least two subgroups, each with a distinctive expression profile. These subtypes proved to be reasonably robust by clustering using two different gene sets: first, a set of 456 cDNA clones previously selected to reflect intrinsic properties of the tumors and, second, a gene set that highly correlated with patient outcome. Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.

Gene expression profiling predicts clinical outcome of breast cancer

Abstract: Breast cancer patients with the same stage of disease can have markedly different treatment responses and overall outcome. The strongest predictors for metastases (for example, lymph node status and histological grade) fail to classify accurately breast tumours according to their clinical behaviour. Chemotherapy or hormonal therapy reduces the risk of distant metastases by approximately one-third; however, 70-80% of patients receiving this treatment would have survived without it. None of the signatures of breast cancer gene expression reported to date allow for patient-tailored therapy strategies. Here we used DNA microarray analysis on primary breast tumours of 117 young patients, and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases ('poor prognosis' signature) in patients without tumour cells in local lymph nodes at diagnosis (lymph node negative). In addition, we established a signature that identifies tumours of BRCA1 carriers. The poor prognosis signature consists of genes regulating cell cycle, invasion, metastasis and angiogenesis. This gene expression profile will outperform all currently used clinical parameters in predicting disease outcome. Our findings provide a strategy to select patients who would benefit from adjuvant therapy.

Statistical significance for genomewide studies

Abstract: With the increase in genomewide experiments and the sequencing of multiple genomes, the analysis of large data sets has become commonplace in biology. It is often the case that thousands of features in a genomewide data set are tested against some null hypothesis, where a number of features are expected to be significant. Here we propose an approach to measuring statistical significance in these genomewide studies based on the concept of the false discovery rate. This approach offers a sensible balance between the number of true and false positives that is automatically calibrated and easily interpreted. In doing so, a measure of statistical significance called the q value is associated with each tested feature. The q value is similar to the well known p value, except it is a measure of significance in terms of the false discovery rate rather than the false positive rate. Our approach avoids a flood of false positive results, while offering a more liberal criterion than what has been used in genome scans for linkage.

A Gene-Expression Signature as a Predictor of Survival in Breast Cancer

Abstract: Background A more accurate means of prognostication in breast cancer will improve the selection of patients for adjuvant systemic therapy. Methods Using microarray analysis to evaluate our previously established 70-gene prognosis profile, we classified a series of 295 consecutive patients with primary breast carcinomas as having a gene-expression signature associated with either a poor prognosis or a good prognosis. All patients had stage I or II breast cancer and were younger than 53 years old; 151 had lymph-node–negative disease, and 144 had lymph-node–positive disease. We evaluated the predictive power of the prognosis profile using univariable and multivariable statistical analyses. Results Among the 295 patients, 180 had a poor-prognosis signature and 115 had a good-prognosis signature, and the mean (±SE) overall 10-year survival rates were 54.6±4.4 percent and 94.5±2.6 percent, respectively. At 10 years, the probability of remaining free of distant metastases was 50.6±4.5 percent in the group with a...

The fundamental role of epigenetic events in cancer

Abstract: Patterns of DNA methylation and chromatin structure are profoundly altered in neoplasia and include genome-wide losses of, and regional gains in, DNA methylation. The recent explosion in our knowledge of how chromatin organization modulates gene transcription has further highlighted the importance of epigenetic mechanisms in the initiation and progression of human cancer. These epigenetic changes -- in particular, aberrant promoter hypermethylation that is associated with inappropriate gene silencing -- affect virtually every step in tumour progression. In this review, we discuss these epigenetic events and the molecular alterations that might cause them and/or underlie altered gene expression in cancer.