Tailoring treatment for ductal intraepithelial neoplasia of the breast according to Ki-67 and molecular phenotype.

BACKGROUND: The post-surgical management of ductal intraepithelial neoplasia (DIN) of the breast is still a dilemma. Ki-67 labelling index (LI) has been proposed as an independent predictive and prognostic factor in early breast cancer. METHODS: The prognostic and predictive roles of Ki-67 LI were evaluated with a multivariable Cox regression model in a cohort of 1171 consecutive patients operated for DIN in a single institution from 1997 to 2007. RESULTS: Radiotherapy (RT) was protective in subjects with DIN with Ki-67 LI ≥ 14%, whereas no evidence of benefit was seen for Ki-67 LI <14%, irrespective of nuclear grade and presence of necrosis. Notably, the higher the Ki-67 LI, the stronger the effect of RT (P-interaction <0.01). Hormonal therapy (HT) was effective in both Luminal A (adjusted hazard ratio (HR)=0.56 (95% CI, 0.33-0.97)) and Luminal B/Her2neg DIN (HR 0.51 (95% CI, 0.27-0.95)). CONCLUSION: Our data suggest that Ki-67 LI may be a useful prognostic and predictive adjunct in DIN patients. The Ki-67 LI of 14% could be a potential cutoff for better categorising this population of women at increased risk for breast cancer and in which adjuvant treatment (RT, HT) should be differently addressed, independent of histological grade and presence of necrosis.

The effect of metformin on apoptosis in a breast cancer presurgical trial.

BACKGROUND: Metformin has been associated with antitumour activity in breast cancer (BC) but its mechanism remains unclear. We determined whether metformin induced a modulation of apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) overall and by insulin resistance status in a presurgical trial. METHODS: Apoptosis was analysed in core biopsies and in surgical samples from 100 non-diabetic BC patients participating in a randomised trial of metformin vs placebo given for 4 weeks before surgery. RESULTS: Eighty-seven subjects (45 on metformin and 42 on placebo) were assessable for TUNEL measurement at both time points. TUNEL levels at surgery were higher than that at baseline core biopsy (P<0.0001), although no difference between arms was noted (metformin arm: median difference surgery-biopsy levels +4%, interquartile range (IQR): 2-12; placebo arm: +2%, IQR: 0-8, P=0.2). Ki67 labelling index and TUNEL levels were directly correlated both at baseline and surgery (Spearman's r=0.51, P<0.0001). In the 59 women without insulin resistance (HOMA index<2.8) ,there was a higher level of TUNEL at surgery on metformin vs placebo (median difference on metformin +4%, IQR: 2-14 vs +2%, IQR: 0-7 on placebo), whereas an opposite trend was found in the 28 women with insulin resistance (median difference on metformin +2%, IQR: 0-6, vs +5%, IQR: 0-15 on placebo, P-interaction=0.1). CONCLUSION: Overall, we found no significant modulation of apoptosis by metformin, although there was a trend to a different effect according to insulin resistance status, with a pattern resembling Ki67 changes. Apoptosis was significantly higher in the surgical specimens compared with baseline biopsy and was directly correlated with Ki67. Our findings provide additional evidence for a dual effect of metformin on BC growth according to insulin resistance status.

A phase-III prevention trial of low-dose tamoxifen in postmenopausal hormone replacement therapy users: the HOT study.

BACKGROUND: Postmenopausal hormone replacement therapy (HRT) relieves menopausal symptoms and may decrease mortality in recently postmenopausal women, but increases breast cancer risk. Low-dose tamoxifen has shown retained activity in phase-II studies. METHODS: We conducted a phase-III trial in 1884 recently postmenopausal women on HRT who were randomly assigned to either tamoxifen, 5 mg/day, or placebo for 5 years. The primary end point was breast cancer incidence. RESULTS: After 6.2 ± 1.9 years mean follow-up, there were 24 breast cancers on placebo and 19 on tamoxifen (risk ratio, RR, 0.80; 95% CI 0.44-1.46). Tamoxifen showed favorable trends in luminal-A tumors (RR, 0.32; 95% CI 0.12-0.86), in HRT users <5 years (RR, 0.35; 95% CI 0.15-0.82) and in women completing at least 12 months of treatment (RR, 0.49; 95% CI 0.23-1.02). Serious adverse events did not differ between placebo and tamoxifen, including, respectively, coronary heart syndrome (6 versus 4), cerebrovascular events (2 versus 5), VTE (2 versus 5) and uterine cancers (3 versus 1). Vasomotor symptoms were 50% more frequent on tamoxifen. CONCLUSIONS: The addition of low-dose tamoxifen to HRT did not significantly reduce breast cancer risk and increased climacteric symptoms in recently postmenopausal women. However, we noted beneficial trends in some subgroups which may deserve a larger study.

Low-dose tamoxifen in the treatment of breast ductal intraepithelial neoplasia: results of a large observational study.

BACKGROUND: Tamoxifen's cost-benefit ratio for breast ductal intraepithelial neoplasia (DIN) is unclear. Since low-dose tamoxifen showed a favorable modulation of breast cancer biomarkers in phase II trials, a monoinstitutional cohort of women with DIN treated with low-dose tamoxifen or no systemic treatment was analyzed. PATIENTS AND METHODS: A total of 309 patients with DIN received low-dose tamoxifen as part of institutional guidelines and were compared with 371 patients with DIN who received no systemic treatment after surgery. RESULTS: Women with estrogen receptor (ER)/progesterone receptor (PgR) >50% DIN who were not treated had a higher incidence of breast events than women on tamoxifen [hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.00-3.12] or women with ER/PgR <50% DIN (HR 1.72; 95% CI 1.14-2.58). Among untreated patients with ER >50% DIN, recurrence was higher in PgR > or =50% DIN than in PgR <50% DIN, whereas it was similar among low PgR (<50%) DIN against which tamoxifen had no effect. No difference in endometrial cancer incidence was noted. CONCLUSIONS: High ER and especially high PgR expression is a significant adverse prognostic indicator of DIN, and low-dose tamoxifen appears to be an active treatment. Women with low-expression ER or PgR DIN do not seem to benefit from tamoxifen. A definitive clinical trial is warranted.

The ying and yang of idebenone: Not too little, not too much - cell death in NQO1 deficient cells and the mouse retina.

Idebenone has recently been investigated as a drug therapy for Leber's hereditary optic neuropathy (LHON), a rare genetic mitochondrial disease that causes rapid and progressive bilateral vision loss. Although several studies have shown that idebenone can promote vision recovery in patients with LHON, the evidence for the efficacy of idebenone is still limited. Idebenone failed to demonstrate superiority over placebo in the primary end-points of the only published randomised, double-blind, placebo-controlled trial. There appears to be a patient-specific response to idebenone with high variability in therapeutic outcomes. A recent study suggested that the cytosolic enzyme NAD(P)H: quinone acceptor oxidoreductase (NQO1) is the major enzyme involved in the activation of idebenone, and the beneficial effects of idebenone are dependent on the expression of NQO1. Here, we confirm the NQO1-dependent activity of idebenone, but we also show, for the first time, that the cytotoxicity of idebenone is linked to cellular expression of NQO1. Upon idebenone administration, cells deficient in NQO1 show a marked decrease in viability in comparison to NQO1 expressing cells, with idebenone causing ROS production and deleterious effects on ATP levels and cell viability. In addition, our data highlights that only cells expressing NQO1 can significantly activate idebenone, indicating that other proposed metabolic activation pathways, such as complex II and glycerol-3-phosphate dehydrogenase, do not play a significant role in idebenone activation. Furthermore, we provide evidence of idebenone-induced toxicity in the retina ex-vivo, which can be explained by the variation of NQO1 expression between different cell types in the mouse retina. Idebenone mediated cell rescue in the rotenone ex vivo model also indicated that this drug has a narrow therapeutic window. These findings will help to guide the development of future therapies and drug delivery strategies including intra-ocular administration. The specific dependence of idebenone activity on NQO1 may also explain the variation in patient outcomes in clinical trials.

Perspectives on comorbidity and cancer in older patients: approaches to expand the knowledge base.

Not only do persons 65 years and older bear a disproportionate burden of cancer, advancing age is associated with increased vulnerability to other age-related health problems. Newly diagnosed older cancer patients who have lived into later years of life may have concurrent ailments (eg, diabetes, chronic obstructive pulmonary disease, heart disease, arthritis, and/or hypertension) that could affect treatment choice, prognosis, and survival. The clinician must often make cancer treatment decisions in the context of an older individual's pre-existing health problems (ie, comorbidity). Ways to produce reliable information on comorbidity that can be effectively used in evaluation of older cancer patients are urgently needed. What is the nature and severity of the older patient's comorbid health problems? How do other age-related conditions influence treatment decisions and the cancer course? How do already compromised older patients tolerate the stress of cancer and its treatment? How are concomitant comorbid conditions managed? At present, no established, valid way to assess comorbidity in older cancer patients exists. Such technology, with a solid conceptual and scientific base, promises a high positive clinical yield to assure quality cancer care for older patients if reliable and valid instruments can be integrated into oncology practice. Much preliminary scientific work must be performed. A synthesis of viewpoints on what to include in comorbidity assessment of older cancer patients and development approaches were expressed in a multidisciplinary working group convened by the National Institute on Aging and the National Cancer Institute. We share the key issues raised regarding complexities of comorbidity assessment and suggestions for scientific inquiry.

Clinical management of superior vena cava syndrome.

SVCS is a relative medical emergency because it is usually the result of partial or complete occlusion of the SVC by a malignant tumor. Obstruction of the SVC is mimicked by few other organic problems. The traditional view of therapy protocols is that treatment can and should be started before an etiologic diagnosis is made. More recent literature holds that difficulties arise when treatment is started before a cause and location are known. The therapy of choice for this localized problem is radiation therapy. High-dose, short-interval radiation is the primary treatment around which diuretics, steroids, and anticoagulants are added as adjuvants. Most patients treated with radiation therapy respond subjectively within 72 hours and show objective signs of relief within 7 days. The overall survival rate is dependent on the underlying malignancy. Nursing care focuses on the early detection of symptoms of SVCS and the emergency nature of the acute phase. Side effects of therapy and nursing care needs result from therapy as well as from the underlying disease. The psychosocial stressors on the patient and the family are an integral part of the nursing care. The goals of nursing management are good supportive care, astute assessment, and monitoring of the patient's condition. Finally, SVCS is a relative medical emergency. This entity has been described for many years, but it is often misunderstood and mismanaged. The goal of medical management is a rapid diagnostic work-up and the administration of palliative radiation therapy to alleviate the symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Relevance of quality of life to clinical nursing practice.

Assessment of quality of life is an important concept for nurses who practice in oncology settings because the physical, psychological, and social well-being of the patients is affected by the disease and its treatment. The use of valid, reliable, and clinically relevant measures of quality of life will facilitate planning of appropriate care and the evaluation of specific interventions.

Informed consent: an overview.

Informed consent is a process, not an isolated incident. It therefore requires that health care professionals approach the process with expert knowledge, open communication, and a willingness to participate in shared decision-making. Table 2 identifies the major ethical and legal issues of informed consent. Legal precedents and professional collaboration will be necessary to further define and refine informed consent. The complexity of treatment regimens, potential system toxicities, and the chronicity of the disease process have fostered the development of a multidisciplinary team approach to the care of oncology patients. Therefore, collaboration is essential to meet the demands of the informed consent process and provide an optimal environment for the oncology nurse to intervene actively as a patient advocate.

Efforts to recruit the economically disadvantaged to national clinical trials.

Clinical trials are vital for the development of state-of-the-art cancer prevention and treatment. A goal for trial recruitment should be to have a representative sample of the total population by gender, race, culture, ethnicity, and socioeconomic status as appropriate. Increased sensitivity to the unique barriers and access to care issues required to achieve a representative sample are necessary. Knowledge and understanding of recruitment problems and strategies to resolve them are developing; however, much more is needed before we can fully address and resolve all of the relevant issues. Nurses have a key role in identification, education, and recruitment of special populations including the SED to clinical trials.

Women's health advocacy: its growth and development in oncology.

Women's health has become a topic of national importance. Advocacy initiatives by consumers, scientists, government officials, health care professionals, industry, and the media have played a role in helping to set this agenda. Much of the current interest in women's health is the result of the women's movement and its interaction with science, medicine, and health care. Emerging consumerism and increasing public knowledge of medical and scientific topics has led to the emergence of patients as individuals seeking to actively make decisions regarding health care options. Nurses should embrace the advocacy movement and, whenever possible, work with patients and their advocates toward their many shared goals.