The role of exercise in cancer treatment: bridging the gap.

In recent years, there has been a burgeoning amount of evidence-based scientific data demonstrating the benefit of exercise during and following cancer treatment. This compelling evidence has resulted in major stakeholders in cancer management, including the American College of Sports Medicine, American Society of Clinical Oncology, National Comprehensive Cancer Network, American Cancer Society, Oncology Nursing Society, and the Commission on Cancer, advocating exercise as an integral component of cancer care. Despite the acknowledgment of exercise as an essential component, it remains virtually absent in routine cancer treatment. This article discusses the role of exercise in cancer treatment utilizing a community-based program. The rationale presented is that a scalable and replicable standard of care model is a plausible avenue to assimilate exercise into routine oncology practice.

Evaluation of developmental toxicity studies of glyphosate with attention to cardiovascular development.

The herbicide glyphosate has undergone multiple safety tests for developmental toxicity in rats and rabbits. The European Commission's 2002 review of available glyphosate data discusses specific heart defects observed in several individual rabbit developmental toxicity studies, but describes the evidence for a potential causal relationship as equivocal. The present assessment was undertaken to analyze the current body of information generated from seven unpublished rabbit studies in order to determine if glyphosate poses a risk for cardiovascular malformations. In addition, the results of six unpublished developmental toxicity studies in rats were considered. Five of the seven rabbit studies (dose range: 10-500 mg/kg/day) were GLP- and testing guideline-compliant for the era in which the studies were performed; a sixth study predated testing and GLP guidelines, but generally adhered to these principles. The seventh study was judged inadequate. In each of the adequate studies, offspring effects occurred only at doses that also caused maternal toxicity. An integrated evaluation of the six adequate studies, using conservative assumptions, demonstrated that neither the overall malformation rate nor the incidence of cardiovascular malformations increased with dose up to the point where severe maternal toxicity was observed (generally ≥150 mg/kg/day). Random occurrences of cardiovascular malformations were observed across all dose groups (including controls) and did not exhibit a dose-response relationship. In the six rat studies (dose range: 30-3500 mg/kg/day), a low incidence of sporadic cardiovascular malformations was reported that was clearly not related to treatment. In summary, assessment of the entire body of the developmental toxicity data reviewed fails to support a potential risk for increased cardiovascular defects as a result of glyphosate exposure during pregnancy.

Incorporating Exercise Into the Cancer Treatment Paradigm.

BACKGROUND: The benefits of exercise for patients with cancer are well documented. However, exercise is still not a standard of care for this population. Several factors contribute to the lack of exercise prescriptions for patients with cancer, including challenges posed by treatment-related side effects, lack of knowledge among healthcare providers and the laypeople, and inadequate resources. OBJECTIVES: This article reviews the benefits of exercise in general and specifically to patients with cancer, discusses the specific challenges and considerations required in recommending exercise to this population, and provides specific recommendations for healthcare providers to incorporate exercise into treatment plans. METHODS: Using a case study exemplar, this article discusses the benefits and challenges to exercise while undergoing treatment for cancer and proposes specific solutions and recommendations. FINDINGS: Oncology practitioners can provide the opportunity for patients to safely engage in exercise with the appropriate resources and trained personnel using a successful model of delivering exercise to patients undergoing treatment for cancer. Exercise improves quality of life in all patients, including those with advanced-stage cancers and those actively receiving treatment.

Phase II study of trastuzumab plus gemcitabine in chemotherapy-pretreated patients with metastatic breast cancer.

We evaluated the efficacy and toxicity of trastuzumab plus gemcitabine in patients with HER2-positive metastatic breast cancer (MBC). Sixty-four patients were enrolled, the majority of whom (95%) had been treated with an anthracycline and a taxane before study enrollment. Eligible women were treated with gemcitabine (1200 mg/m(2) weekly for 2 weeks with the third week off on a 21-day cycle) plus weekly doses of trastuzumab (4-mg/kg loading dose; 2 mg/kg thereafter) until disease progression. The median patient age was 55 years, and the median number of previously administered (including adjuvant) chemotherapy regimens was 3. Twenty-two patients were scored as 2+ for HER2 expression by immunohistochemistry; 39 patients scored 3+. Three patients were assessed as HER2-negative on central pathology review and were ineligible for evaluation. Fifty-nine of the 61 patients remained evaluable for response. The objective response rates were 38% in the intent-to-treat population (23 of 61) and 44% among the 39 patients with HER2 3+ expression. The median response duration was 5.8 months, median overall survival was 14.7 months, and median time to disease progression was 5.8 months. Trastuzumab plus gemcitabine was well tolerated. No cases of clinical congestive heart failure occurred. Grade 3/4 toxicities included asthenia in 4 patients, fever in 4, neutropenia in 18, dyspnea in 6, abdominal or back pain in 3, and edema and nausea in 1 patient each. The combination of trastuzumab plus gemcitabine appears to be well tolerated and effective for patients with HER2-positive MBC previously treated with chemotherapy.

Phase II trial of gemcitabine plus trastuzumab in metastatic breast cancer patients previously treated with chemotherapy: preliminary results.

Preliminary results of a phase II study of gemcitabine plus trastuzumab in previously treated (up to 3 previous regimens) metastatic breast cancer patients are presented. Patients had histologically confirmed metastatic breast cancer, with 2+ or 3+ tumor HER2 expression. Treatment consisted of gemcitabine 1200 mg/m2 over 30 minutes intravenously on days 1 and 8 every 21 days, and trastuzumab 4 mg/kg over 90 minutes, followed by 2 mg/kg infused over 30 minutes weekly. Treatment was continued until disease progression or unacceptable toxicity occurred. Preliminary results are available on the first 38 patients enrolled. Median patient age was 53 years, 53% had estrogen receptor/progesterone receptor-positive disease, and HER2 staining was 2+ in 39% and 3+ in 61% of patients. There was a median of 3 previously administered (including adjuvant) chemotherapy regimens, and a median of 4.5 treatment cycles per patient has been administered so far. Twelve patients (32%) have had an objective partial response, with a median response duration of 8.6 months. Median time to disease progression is 6.7 months to date, with a median overall survival of 10.2 months. No unexpected toxicities or grade 4 nonhematologic toxicities have been observed; 2 patients developed grade 4 neutropenia and 1 patient had febrile neutropenia. Thus, gemcitabine/ trastuzumab resulted in an encouraging 32% response rate, given the heavily pretreated patient population. Tolerability was good overall, with no unexpected side effects observed.

HSP90alpha, HSP90beta, and p53 expression following in vitro hyperthermia exposure in gestation day 10 rat embryos.

The studies presented here are aimed at understanding the expression of p53, HSP90alpha, and HSP90beta in gestation day (GD) 10 CD rat embryos. GD 10 rat embryos were exposed in vitro to 37 degrees C or 42 degrees C for 15 min, then cultured at 37 degrees C for 0.5, 1, 3, or 5 h. Immunohistochemistry was performed on formalin-fixed, paraffin embedded, sectioned embryos for p53, HSP90alpha, or HSP90beta expression. p53 expression was minimal in control embryos but was induced with heat exposure. Maximum expression of p53 was observed in rostral tissues, e.g., the optic vesicle, rostral neuroepithelium, and mature (rostral) somites 3 and 5 h after heat exposure. Expression of p53 in the caudal region, such as in mid and caudal neuroepithelium, immature (caudal) somites, and presomitic mesoderm, was moderate compared to rostral areas. No p53 expression was observed in the heart under any condition. The rostral-caudal gradient of p53 expression was not observed for HSP90alpha expression. HSP90alpha was induced in heat-exposed embryos beginning at 1 h, predominantly in neural tube and optic vesicle. Moderate but increased expression was observed in the somites of heat-exposed embryos at 3 and 5 h. Expression of p53 was primarily nuclear while HSP90alpha expression was mostly cytoplasmic. No clear association was observed between heat-induced HSP90alpha and p53 expression. HSP90beta was expressed extensively in control and heat-exposed embryos. Results indicate that heat induces p53 and HSP90alpha expression, but not HSP90beta expression, and that HSP90alpha induction is not likely to be involved in p53 regulation in mammalian embryos.

Community-based FitSTEPS for life exercise program for persons with cancer: 5-year evaluation.

PURPOSE: To determine the effects of a community-based program of exercise on quality of life (QOL) of persons with cancer over time. METHODS: Participants were referred by their physician to participate in an individualized program of exercise at one of 14 community centers. The Medical Outcomes Survey, Short Form, version 2.0 (SF-36) was used to assess QOL. Individual participants were monitored for 2 years. Data collection took place at baseline, every 3 months months during year 1, and every 6 months during year 2. RESULTS: Enrolled participants (n = 701) had been diagnosed with different cancers and were at all stages; 177 completed data collection for 2 years. One-way analysis of variance (n = 177) supported the positive impact of exercise on QOL over time. Significant subscale scores of the SF-36, including Physical Function (F = 2.13, P ≤ .047), Role Physical (F = 3.78, P ≤ .001), Vitality (F = 5.97, P ≤ .001), Social Function (F = 4.46, P ≤ .001), Role Emotional (F = 2.56, P ≤ .01), Mental Health (F = 2.16, P ≤ .05), and General Health (F = 3.42, P ≤ .01), were sustainable over time. CONCLUSION: This research introduces the concept of a long-term community-based program of individualized exercise as a feasible and effective intervention to improve QOL for persons with all stages of cancer. Improvements, noted at the 3-month time point, appear to be sustainable for extended time (24 months). Attrition is problematic and needs to be addressed. Results from this study have significance for practice recommendations and health policy reimbursement issues.

Model for a community-based exercise program for cancer survivors: taking patient care to the next level.

This article describes the development and refinement of a not-for-profit, community-based exercise program, the Cancer Foundation For Life (CFFL), designed to improve quality of life (QOL) for persons with cancer, regardless of type or stage of disease. Beginning in 2001, policies and procedures were developed, and personnel were hired and trained. Program evaluation measured safety, exercise adherence, demographic variables, and QOL. CFFL had nearly 3,000 referrals and handled more than 66,000 patient encounters in 2010. Financial and social resources for the program have been established through collaboration with existing institutions (churches, cancer centers, hospitals, and community centers), in conjunction with community support. American College of Sports Medicine guidelines presented at the ASCO 2010 meeting recommend exercise for persons with cancer. The CFFL program provides a cost-effective and safe exercise program for persons with all types and stages of cancer that meets these recommended guidelines.

An overview of children as a special population--relevance to predictive biomarkers.

There has been an increasing focus on children as a special population in the fields of toxicology and epidemiology. At the same time, there has been considerable improvement in the technology for defining normal development and pathways of pathogenesis. Increased support of these areas has culminated in stronger research programs and greater professional involvement in addressing the specific challenges of applying new techniques and data to the improvement of children's health. Part of these challenges relates to the ever changing environment of the child. Not only does a child's anatomy, physiology, and metabolism change with time, but their lifestyle and awareness change as well. All of these can have a significant impact on a child's exposure and the potential of that exposure to have an effect on health and development. This paper will provide a brief overview of the susceptibility of the child relative to sensitive developmental life stages, the changing nature of exposure parameters during development, and how these factors can impact the relevance of predictive biomarkers of chemical toxicity in children.

Effects of hyperthermia and boric acid on skeletal development in rat embryos.

BACKGROUND: The individual effects of boric acid (BA) and hyperthermia on the development of the axial skeleton have been reported previously. Both cause an increased incidence of axial skeletal defects including a decrease in the total number of ribs and vertebrae. Because of the similarity in the effects of the two agents, we examined their interaction when given in combination to pregnant rats on gestational day (GD) 10. METHODS: Dams were treated on GD 10 with BA (0, 250, or 500 mg/kg) and hyperthermia (37, 41, or 42 degrees C) and allowed to deliver their pups. Doses of BA were based on results from a dose-finding study. Litters were evaluated on postnatal days (PND) 1 and 3 for number, gender, and weight of pups. On PND3, pups were examined externally and viscerally, and double-stained for skeletal evaluation. RESULTS: A dose-dependent, statistically significant increase in fetal skeletal defects was seen on PND 3 with BA or hyperthermia alone with even greater effects when given in combination. Defects included rib and vertebral fusions, split vertebral centra in the thoracic and lumbar areas, and a decrease in the total number of ribs and vertebrae. CONCLUSIONS: The increased incidence of skeletal defects resulting from combined exposure to hyperthermia and BA was additive for segmentation defects and synergistic for the reduction in numbers of vertebrae.

Overview: Using mode of action and life stage information to evaluate the human relevance of animal toxicity data.

A complete mode of action human relevance analysis--as distinct from mode of action (MOA) analysis alone--depends on robust information on the animal MOA, as well as systematic comparison of the animal data with corresponding information from humans. In November 2003, the International Life Sciences Institute's Risk Science Institute (ILSI RSI) published a 2-year study using animal and human MOA information to generate a four-part Human Relevance Framework (HRF) for systematic and transparent analysis of MOA data and information. Based mainly on non-DNA-reactive carcinogens, the HRF features a "concordance" analysis of MOA information from both animal and human sources, with a focus on determining the appropriate role for each MOA data set in human risk assessment. With MOA information increasingly available for risk assessment purposes, this article illustrates the further applicability of the HRF for reproductive, developmental, neurologic, and renal endpoints, as well as cancer. Based on qualitative and quantitative MOA considerations, the MOA/human relevance analysis also contributes to identifying data needs and issues essential for the dose-response and exposure assessment steps in the overall risk assessment.