Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030.

BACKGROUND: We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy. PATIENTS AND METHODS: We identified responders (RCB 0/1) and matched non-responders (RCB 2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel versus cisplatin in TNBC. We collected plasma samples at baseline, 3 weeks and 12 weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence. RESULTS: Of 139 patients, 68 had complete samples and no additional neoadjuvant chemotherapy. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000 variants) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3 and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10-4 (range 7.9 × 10-7-4.9 × 10-1). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10 of 11 patients with RCB 0, 3 of 8 with RCB 1, 4 of 15 with RCB 2 and 0 of 4 with RCB 3. Among six patients with known recurrence, five had persistent ctDNA at week 12. CONCLUSIONS: Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine whether ctDNA-guided approaches can improve outcomes.

TBCRC 030: a phase II study of preoperative cisplatin versus paclitaxel in triple-negative breast cancer: evaluating the homologous recombination deficiency (HRD) biomarker.

BACKGROUND: Cisplatin and paclitaxel are active in triple-negative breast cancer (TNBC). Despite different mechanisms of action, effective predictive biomarkers to preferentially inform drug selection have not been identified. The homologous recombination deficiency (HRD) assay (Myriad Genetics, Inc.) detects impaired double-strand DNA break repair and may identify patients with BRCA1/2-proficient tumors that are sensitive to DNA-targeting therapy. The primary objective of TBCRC 030 was to detect an association of HRD with pathologic response [residual cancer burden (RCB)-0/1] to single-agent cisplatin or paclitaxel. PATIENTS AND METHODS: This prospective phase II study enrolled patients with germline BRCA1/2 wild-type/unknown stage I-III TNBC in a 12-week randomized study of preoperative cisplatin or paclitaxel. The HRD assay was carried out on baseline tissue; positive HRD was defined as a score ≥33. Crossover to an alternative chemotherapy was offered if there was inadequate response. RESULTS: One hundred and thirty-nine patients were evaluable for response, including 88 (63.3%) who had surgery at 12 weeks and 51 (36.7%) who crossed over to an alternative provider-selected preoperative chemotherapy regimen due to inadequate clinical response. HRD results were available for 104 tumors (74.8%) and 74 (71.1%) were HRD positive. The RCB-0/1 rate was 26.4% with cisplatin and 22.3% with paclitaxel. No significant association was observed between HRD score and RCB response to either cisplatin [odds ratio (OR) for RCB-0/1 if HRD positive 2.22 (95% CI: 0.39-23.68)] or paclitaxel [OR for RCB-0/1 if HRD positive 0.90 (95% CI: 0.19-4.95)]. There was no evidence of an interaction between HRD and pathologic response to chemotherapy. CONCLUSIONS: In this prospective preoperative trial in TNBC, HRD was not predictive of pathologic response. Tumors were similarly responsive to preoperative paclitaxel or cisplatin chemotherapy.

Dendritic cells retrovirally transduced with a model antigen gene are therapeutically effective against established pulmonary metastases.

Dendritic cells (DCs) are bone marrow-derived leukocytes that function as potent antigen presenting cells capable of initiating T cell-dependent responses from quiescent lymphocytes. DC pulsed with tumor-associated antigen (TAA) peptide or protein have recently been demonstrated to elicit antigen-specific protective antitumor immunity in a number of murine models. Transduction of DCs with TAA genes may allow stable, prolonged antigen expression as well as the potential for presentation of multiple, or unidentified, epitopes in association with major histocompatibility complex class I and/or class II molecules. To evaluate the potential efficacy of retrovirally transduced DCs, bone marrow cells harvested from BALB/c mice were transduced with either a model antigen gene encoding beta-galactosidase (beta-gal) or a control gene encoding rat HER-2/neu (Neu) by coculture with irradiated ecotropic retroviral producer lines. Bone marrow cells were differentiated into DC in vitro using granulocyte/macrophage colony-stimulating factor and interleukin-4. After 7 d in culture, cells were 45-78% double positive for DC phenotypic cell surface markers by FACS(R) analysis, and DC transduced with beta-gal were 41-72% positive for beta-gal expression by X-gal staining. In addition, coculture of beta-gal transduced DC with a beta-gal-specific T cell line (CTLx) resulted in the production of large amounts of interferon-gamma, demonstrating that transduced DCs could process and present endogenously expressed beta-gal. DC transduced with beta-gal and control rat HER-2/neu were then used to treat 3-d lung metastases in mice bearing an experimental murine tumor CT26.CL25, expressing the model antigen, beta-gal. Treatment with beta-gal-transduced DC significantly reduced the number of pulmonary metastatic nodules compared with treatment with Hank's balanced salt solution or DCs transduced with rat HER-2/neu. In addition, immunization with beta-gal-transduced DCs resulted in the generation of antigen-specific cytotoxic T lymphocytes (CTLs), which were significantly more reactive against relevant tumor targets than CTLs generated from mice immunized with DCs pulsed with the Ld-restricted beta-gal peptide. The results observed in this rapidly lethal tumor model suggest that DCs transduced with TAA may be a useful treatment modality in tumor immunotherapy.

Evidence supporting nutritional interventions for persons in early stage Alzheimer's disease (AD).

The purpose of this paper is to grade research evidence supporting nutritional interventions for persons with early stage dementias and to report the recommendations of a consensus panel. Thirty four studies were reviewed in the areas of dietary restriction, antioxidants, and Mediterranean diet with strong support from epidemiological studies found in all three areas. The body of evidence to support nutritional interventions in the prevention and treatment of AD is growing and has potential as a treatment modality following translational studies.

Genome duplication in soybean (Glycine subgenus soja).

Restriction fragment length polymorphism mapping data from nine populations (Glycine max x G. soja and G. max x G. max) of the Glycine subgenus soja genome led to the identification of many duplicated segments of the genome. Linkage groups contained up to 33 markers that were duplicated on other linkage groups. The size of homoeologous regions ranged from 1.5 to 106.4 cM, with an average size of 45.3 cM. We observed segments in the soybean genome that were present in as many as six copies with an average of 2.55 duplications per segment. The presence of nested duplications suggests that at least one of the original genomes may have undergone an additional round of tetraploidization. Tetraploidization, along with large internal duplications, accounts for the highly duplicated nature of the genome of the subgenus. Quantitative trait loci for seed protein and oil showed correspondence across homoeologous regions, suggesting that the genes or gene families contributing to seed composition have retained similar functions throughout the evolution of the chromosomes.

Effect of beta-casomorphins and analogs on insulin release in dogs.

Opioid-active substances have been isolated from bovine beta-casein peptone (beta-casomorphin). Since the ingestion of beta-casomorphin-containing foodstuff elicits an increase in postprandial insulin release, the present study was designed to determine the effect of iv infused beta-casomorphins on insulin release. The infusion of beta-casomorphin-7, -5, -4, and -3 did not alter basal insulin secretion. During prestimulation of insulin release with amino acids and glucose the infusion of beta-casomorphin-7, -5, -4, and -3 at a dose of 1 nmol/ kg . h augmented insulin release, whereas at a concentration of 100 nmol/kg . h no further stimulatory effect was observed except for the infusion of beta-casomorphin-4. In comparison, the infusion of morphine elicited a potentiation of insulin release at the lower dose, whereas no effect was observed at the higher infusion rate. Leucine-enkephalin had no effect at the lower dose but elicited an inhibitory effect at the higher rate. The infusion of opiate-active and inactive analogs of beta-casomorphin-4 resulted in a loss of its stimulatory effect, indicating that the full tetrapeptide structure of the molecule is important for its stimulatory activity on beta-cell secretion. All stimulatory and inhibitory effects of the opioid-active substances were blocked by the specific opiate-receptor antagonist naloxone. Additionally, the present data support the concept that beta-cell secretion is stimulated by mu-receptor activation and inhibited by delta-receptor activation. The K-receptor antagonist ethyl-ketocyclazocine did not alter insulin secretion. The fact that iv administered beta-casomorphins stimulate insulin release raises the possibility that ingested food-derived opioid-active substances modulate pancreatic endocrine function also after their absorption, provided the doses employed in the present study reflect physiological concentrations of circulating beta-casomorphins.

Early experience with 'new federalism' in health insurance regulation.

The authors monitored the implementation of the Health Insurance Portability and Accountability Act (HIPAA) from 1997 to 1999. Regulators in all states and relevant federal agencies were interviewed and applicable laws and regulations studied. The authors found that HIPAA changed legal protections for consumers' health coverage in several ways. They examine how the process of regulating such coverage was affected at the state and federal levels and under an emerging partnership of the two. Despite some early implementation challenges, HIPAA's successes have been significant, although limited by the law's incremental nature.

Outcome indicators for direct and indirect caregiving.

Informal caregiving and outcomes for caregiving are an important part of health care and of particular importance in nursing. The purpose of this research is to report the results of a survey mailed to nursing experts for validation of the outcome labels Caregiver Role Performance: Direct Care and Caregiver Role Performance: Indirect Care and their accompanying indicators. Experts were asked to rate how important the identified indicators were for assessing those two outcomes. In addition, the respondents were asked to what extent nursing interventions influence the achievement of each identified indicator for Caregiver Role Performance: Direct Care and Caregiver Role Performance: Indirect Care. In general, the validity of the concept analysis work by the caregiver focus group was supported. Ten indicators for Caregiver Performance: Direct Care were retained, 1 was dropped that was considered most appropriate for indirect care, and 3 new indicators were added to reflect the nurse experts surveyed. For Caregiver Performance: Indirect Care, all of the indicators were retained.

Evaluating the cost of one telehealth application connecting an acute and long-term care setting.

This article describes a study of the costs of a pilot telemedicine chronic wound consultation clinic. Cost minimization analysis is the technique used to examine the costs of the clinic. The components of cost analysis include the fixed costs of personnel and equipment and the indirect costs of circuit and line charges. Cost avoidance is also examined. Cost avoidance evaluates what costs were avoided by the use of the telemedicine clinic. Additionally, the cost perspectives of the consulting agency, the referring agency, and the patient are examined. The average cost of a chronic wound consultation was $136.16 (acute care perspective). Costs of a traditional face-to-face consultation, if the residents were transported to the acute care facility would be $246.28. Fifteen telehealth consultations per month were used to determine per consultation costs for line charges and depreciation/maintenance costs. In this pilot study, a cost savings was realized and patients benefited. Increased volume will help to offset the cost of the equipment depreciation and maintenance and make telehealth chronic wound consultations more cost effective.

Special care units for people with Alzheimer's disease. Only for the privileged few?

The number of Special Care Units (SCUs) for people with Alzheimer's disease (AD) in nursing homes have increased dramatically in the past 10 years. Despite the rapid increase in number of SCUs and the concern that most SCUs report higher costs than traditional nursing home units where residents with AD are integrated with cognitively intact residents, the evaluation of costs has been largely unsystematic and noncomparative. Studies are urgently needed to assess comparative costs so that administrators and policy makers can make informed decisions. This article reviews studies that examine the costs of care in SCUs and presents cost-related data comparing the outcomes of care for residents with AD on a SCU and on traditional units in one long-term care setting.

How accurate are chronic wound assessments using interactive video technology?

This project examined the accuracy of chronic wound assessments made using an interactive, video telecommunications system (Teledoc 5000, NEC America, Inc., Irving, TX) by comparing a nurse expert's in-person wound assessments with wound assessments made from taped Teledoc sessions. Wound assessments determined the absence or presence of nine wound characteristics instrumental in guiding treatment (e.g., tunneling, undermining, granulation tissue, necrotic tissue, epithelial tissue, purulent exudate, erythema, edema, induration). A sample of 13 paired wound observations was analyzed. The accuracy of the Teledoc technology was examined by calculating the amount of agreement between the in-person assessments and the taped Teledoc assessments for each of the nine characteristics. Agreement for eight of the nine wound characteristic exceeded 75%, suggesting this telehealth medium does not alter wound assessment data, which are essential in guiding treatment decisions. In addition to connecting the remotely based nurse with nursing expertise to improve patient care, telehealth technology seemed to increase the remotely-based nurses' knowledge of wound assessment and treatment as well.

A nursing application of telecommunications. Measurement of satisfaction for patients and providers.

Consumer and provider satisfaction is key to the continued use and expansion of telehealth technology. This pilot study compared satisfaction of providers and patients with wound consultations done in person with those done via real-time interactive video technology. Eleven telehealth consultations with a nurse expert were immediately followed by an in-person consultation with a second nurse expert. Satisfaction questionnaires were administered to patients, referring nurses, and the consultant nurse expert following both the in-person consultation and the telehealth consultation. The referring nurses (100%) were satisfied with both the telehealth and in-person consultations, noting the ability to provide better care for their patients. The patients (55%) were "very satisfied" with the telehealth consultations versus 40% satisfied with the in-person consultations. Difficulty in hearing for the patients was equal in both groups, which resulted in changes in the consultation process. The patients' difficulty in seeing the telehealth consultant was addressed through larger screens and strategic positioning to provide easier viewing for the patient and providers. The telehealth nurse consultant was satisfied overall but had some difficulty communicating. This pilot study helped provide useful information for both the telehealth and in-person consultations.

The implementation of nursing diagnoses. The Iowa Veterans Home experience.

This article has reviewed the process of implementing nursing diagnoses in one long-term care agency. Nursing diagnoses improved nursing process skills, made problem identification more accurate, and aided the identification of nursing interventions and desired outcomes. Nursing diagnoses have become the organizing framework for quality assurance, staff development, specialization and consultation, and computer applications. The presence of a professional model of nursing practice facilitated the use of nursing diagnoses. Prior to implementing nursing diagnoses, IVH nurses had defined the scope of nursing practice and formed a committee structure for decision-making by all RNs. The structure included mechanisms for collective and individual accountability. All nurses participated in the decision to use nursing diagnoses in their practice. Each nurse had the opportunity to influence the process of change. The process of implementing nursing diagnoses at IVH continues. Nurses recognize the need to establish the validity of each diagnostic statement. Skill with the diagnostic process is expected to improve. Nurses also recognize the need to test interventions for specific diagnoses. The standard nomenclature will continue to be used for the improvement of nursing practice and for nursing department programming. The use of nursing diagnoses is the basis of the continued development of a professional model of nursing practice.

Adoption of a research-based practice for treatment of pressure ulcers.

Evaluation of a skin care protocol for the treatment of pressure ulcers in this institution showed that practitioners did adopt research-based practice. This change in practice was associated with a corresponding decrease in costs for treatment. More pressure ulcers received treatment after implementation of the protocol. Furthermore, the majority of pressure ulcers were being treated with wound care modalities identified by research as supportive of healing. Use of antiseptic agents harmful to the healing process declined as did use of topical agents with little research base to support their efficacy. The shift to practice patterns that were more consistent with research findings was associated with a corresponding decrease in costs for pressure ulcer treatment. Factors in this situation that lead to the positive outcome of knowledge utilization were an organizational model that promoted accountability of individual practitioners, staff participation in decision making, agency regard for research, and consultation with a nurse expert. Informal individual utilization of knowledge related to the treatment of pressure ulcers reinforced use of the research-based practice and expedited formal implementation of a policy/procedure related to their treatment. The process of knowledge utilization that occurred in this institution provides a prototype of how research can be translated into practice. Although limited to one specific clinical problem, the results of this process can be applied to any clinical condition where there are sufficient research findings to support development of recommendations for practice.

Alzheimer's special care units.

An overview of Alzheimer's special care units is provided, including the several models that have been used to guide their development. Philosophy and programming, physical and social environments, staff selection and training, admission and discharge criteria, family programming, and quality and cost features are described. Evaluation and research of special units and interventions for residents with Alzheimer's, their family members and staff caregivers are discussed.