Probing the particulate microstructure of the aerodynamic particle size distribution of dry powder inhaler combination products.

The in-vitro aerosol performance of two combination dry powder inhaler (DPI) products, Foster® NEXThaler® and Seretide® Diskus® were investigated with single particle aerosol mass spectrometry (SPAMS). The in-vitro pharmaceutical performance is markedly different for both inhalers. Foster® NEXThaler® generates a higher fine particle fraction (FPF <5 µm) and a much higher relative extra fine particle fraction (eFPF <2 µm). In terms of the composition of the aerodynamic particle size distribution (APSD), it could be verified with SPAMS that overall Foster® NEXThaler® emits a significantly higher number of fine and extra fine particles with a median aerodynamic diameter (MAD) of 2.1 µm while Seretide® Diskus® had a larger MAD of 3.1 µm. Additionally, the interactions between the two active pharmaceutical ingredients (APIs) in both products are different. While Seretide® Diskus® emits a significant (37%) number of co-associated API particles, only a negligible number of co-associated API particles were found in Foster® NEXThaler® (<1%). A major difference with Foster® NEXThaler® is that it contains magnesium stearate (MgSt) as a second excipient besides lactose in a so-called 'dual excipient' platform. The data generated using SPAMS suggested that nearly all of the beclomethasone dipropionate particles in Foster® NEXThaler® also contain MgSt and must therefore be co-associated with this additional excipient. This may help explain why beclomethasone dipropionate in Foster® NEXThaler® forms less particle co-associations with the second API, formoterol fumarate, shows a lower cohesive strength in respect to beclomethasone itself and why both APIs exhibit superior detachment from the carrier as evidenced by the increased eFPF and smaller MAD.

Developing a risk-based trading scheme for cattle in England: farmer perspectives on managing trading risk for bovine tuberculosis.

This paper examines farmer attitudes towards the development of a voluntary risk-based trading scheme for cattle in England as a risk mitigation measure for bovine tuberculosis (bTB). The research reported here was commissioned to gather evidence on the type of scheme that would have a good chance of success in improving the information farmers receive about the bTB risk of cattle they buy. Telephone interviews were conducted with a stratified random sample of 203 cattle farmers in England, splitting the interviews equally between respondents in the high-risk area and low-risk area for bTB. Supplementary interviews and focus groups with farmers were also carried out across the risk areas. Results suggest a greater enthusiasm for a risk-based trading scheme in low-risk areas compared with high-risk areas and among members of breed societies and cattle health schemes. Third-party certification of herds by private vets or the Animal and Plant Health Agency were regarded as the most credible source, with farmer self-certification being favoured by sellers, but being regarded as least credible by buyers. Understanding farmers' attitudes towards voluntary risk-based trading is important to gauge likely uptake, understand preferences for information provision and to assist in monitoring, evaluating and refining the scheme once established.

Sub-lethal coral stress: detecting molecular responses of coral populations to environmental conditions over space and time.

In order for sessile organisms to survive environmental fluctuations and exposures to pollutants, molecular mechanisms (i.e. stress responses) are elicited. Previously, detrimental effects of natural and anthropogenic stressors on coral health could not be ascertained until significant physiological responses resulted in visible signs of stress (e.g. tissue necrosis, bleaching). In this study, a focused anthozoan holobiont microarray was used to detect early and sub-lethal effects of spatial and temporal environmental changes on gene expression patterns in the scleractinian coral, Montastraea cavernosa, on south Florida reefs. Although all colonies appeared healthy (i.e. no visible tissue necrosis or bleaching), corals were differentially physiologically compensating for exposure to stressors that varied over time. Corals near the Port of Miami inlet experienced significant changes in expression of stress responsive and symbiont (zooxanthella)-specific genes after periods of heavy precipitation. In contrast, coral populations did not demonstrate stress responses during periods of increased water temperature (up to 29°C). Specific acute and long-term localized responses to other stressors were also evident. A correlation between stress response genes and symbiont-specific genes was also observed, possibly indicating early processes involved in the maintenance or disruption of the coral-zooxanthella symbiosis. This is the first study to reveal spatially- and temporally-related variation in gene expression in response to different stressors of in situ coral populations, and demonstrates that microarray technology can be used to detect specific sub-lethal physiological responses to specific environmental conditions that are not visually detectable.

Exposures in early life: associations with DNA promoter methylation in breast tumors.

There is evidence that epigenetic changes occur early in breast carcinogenesis. We hypothesized that early-life exposures associated with breast cancer would be associated with epigenetic alterations in breast tumors. In particular, we examined DNA methylation patterns in breast tumors in association with several early-life exposures in a population-based case-control study. Promoter methylation of E-cadherin, p16 and RAR-ß2 genes was assessed in archived tumor blocks from 803 cases with real-time methylation-specific PCR. Unconditional logistic regression was used for case-case comparisons of those with and without promoter methylation. We found no differences in the prevalence of DNA methylation of the individual genes by age at menarche, age at first live birth and weight at age 20. In case-case comparisons of premenopausal breast cancer, lower birth weight was associated with increased likelihood of E-cadherin promoter methylation (OR = 2.79, 95% CI, 1.15-6.82, for ⩽2.5 v. 2.6-2.9 kg); higher adult height with RAR-ß2 methylation (OR = 3.34, 95% CI, 1.19-9.39, for ⩾1.65 v. <1.60 m); and not having been breastfed with p16 methylation (OR = 2.75, 95% CI, 1.14-6.62). Among postmenopausal breast cancers, birth order was associated with increased likelihood of p16 promoter methylation. Being other than first in the birth order was inversely associated with likelihood of ⩾1 of the three genes being methylated for premenopausal breast cancers, but positively associated with methylation in postmenopausal women. These results suggest that there may be alterations in methylation associated with early-life exposures that persist into adulthood and affect breast cancer risk.

The impact of obesity on receipt of adjuvant chemotherapy for breast cancer in the National Comprehensive Cancer Network (NCCN) centers.

Disparities in the receipt of adjuvant chemotherapy for early stage breast cancer is an important factor influencing mortality. We investigated whether greater body mass index (BMI) decreases receipt of adjuvant chemotherapy among women with operable breast cancer. In the NCCN breast cancer outcomes database, we identified women aged ≤ 70 with newly diagnosed stage I, II, or III breast cancer between 1997 and 2007, for whom use of adjuvant chemotherapy was classified as either standard-of-care or discretionary based on their clinical characteristics. Body mass index was assessed in categories (<18.5 kg/m(2) [underweight], 18.5 to <25 kg/m(2) [normal], 25 to <30 kg/m(2) [overweight], 30-39 kg/m(2) [obese], ≥ 40 kg/m(2) [extreme obese]). Multivariable logistic regression analysis was used to examine the association between BMI and receipt of chemotherapy in each classification group. 9,527 women were eligible for the study; 40% normal weight or less; 31% overweight; 24% obese; and 5% extremely obese. In multivariable analysis, there was no significant association between BMI and receipt of chemotherapy in either classification group. Among women for whom chemotherapy would be considered standard-of-care, older age (P < 0.001), comorbidity (P < 0.001), and non-Hispanic black ethnicity (P = 0.002) were associated with a lower likelihood of receipt of chemotherapy; however, the effect of ethnicity was not modified by obesity. Among women treated for operable breast cancer in the NCCN centers, BMI had no impact on receipt of adjuvant chemotherapy and did not modify the lower likelihood of chemotherapy among non-Hispanic black patients. Further investigation is needed into other factors that contribute to patient disparities in the receipt of chemotherapy in major academic centers.

Potential sources of Campylobacter infection on chicken farms: contamination and control of broiler-harvesting equipment, vehicles and personnel.

AIMS: To test the efficacy of enhanced biosecurity measures on poultry farms for reducing environmental contamination with Campylobacter during partial depopulation of broiler flocks prior to normal slaughter age. The study has also evaluated the risk of infection from live-bird transport crates that are routinely cleaned at the slaughterhouse, but may remain contaminated. METHODS AND RESULTS: On-farm sampling and Campylobacter isolation was undertaken to compare the prevalence of contamination on vehicles, equipment and catching personnel during farm visits that took place under normal or enhanced biosecurity. Campylobacters were found in almost all types of sample examined and enhanced biosecurity reduced the prevalence. However, the additional measures failed to prevent colonisation of the flocks. For transport crates, challenge trials involved exposure of broilers to commercially cleaned crates and genotyping of any campylobacters isolated. The birds were rapidly colonised with the same genotypes as those isolated from the cleaned crates. CONCLUSIONS: The enhanced biosecurity measures were insufficient to prevent flock colonisation, and the problem was exacerbated by inadequate cleaning of transport crates at the slaughterhouse. SIGNIFICANCE AND IMPACT OF THE STUDY: Current commercial practices in the United Kingdom facilitate the spread of campylobacters among broiler chicken flocks. Prevention of flock infection appears to require more stringent biosecurity than that studied here.

Sources and spread of thermophilic Campylobacter spp. during partial depopulation of broiler chicken flocks.

The practice of partial depopulation or thinning (early removal of a portion of birds from a commercial broiler flock) is a reported risk factor for Campylobacter colonization of residual birds because of the difficulty in maintaining biosecurity during the thinning process. The effect of this practice was studied in detail for 51 target flocks, each at a different growing farm belonging to one of seven major poultry companies throughout the United Kingdom. On 21 of these farms, the target flock was already colonized by Campylobacter, and at slaughter all cecal samples examined were positive, with a mean of 8 log CFU/g. An additional 27 flocks became positive within 2 to 6 days of the start of thinning and had similarly high levels of cecal carriage at slaughter. Just before the thinning process, Campylobacter was isolated frequently from the farm driveways, transport vehicles, equipment, and personnel. Strains from seven farms on which flocks became colonized after thinning were examined by pulsed-field gel electrophoresis typing. An association was found between strains occurring at specific sampling sites and those isolated subsequently from the thinned flocks. The results indicated that particular strains had spread from one farm to another when the farms were jointly owned by the same company and employed the same bird-catching teams and/or vehicles. These results highlight the need for better hygiene control in relation to catching equipment and personnel and more effective cleaning and disinfection of vehicles and bird-transport crates.

Powder compaction properties of sodium starch glycolate disintegrants.

The compaction behavior of three "as supplied" commercially available grades of sodium starch glycolate (SSG), Explotab, Primojel, and Vivastar P, was investigated at compression speeds of 0.17 and 30 mm/sec. The results suggested that the three "as supplied" materials exhibit different compression and compaction behavior. Primojel and Explotab exhibited similar compactibility, whereas Vivastar P produced compacts of poor integrity. This behavior was not mirrored in the compressibility of the powders, where Vivastar P and Explotab exhibited similar performance. The materials were studied using x-ray diffraction, scanning electron microscopy, Carr's compressibility index, and swelling volume. In terms of material characteristics, all the products exhibited similar swelling in water. Primojel and Explotab retained most of the crystallographic order from the parent potato starch and exhibited comparable particle surface topographies. Vivastar P contained the lowest moisture level. However, it is not clear if the poor compactibility of Vivastar P is due to differences in moisture content, the reduced surface topography, or subtle differences in the SSG polymer structures (substitution, cross-linking, and crystallinity). Overall, even though the three commercial grades of sodium starch glycolate are successfully used as disintegrants, they do exhibit differences in their "as supplied" powder mechanical properties: Primojel and Explotab exhibit similar compactibility, whereas Vivastar P is poorly compactable but exhibits similar compressibility to Explotab. These observations may have implications when formulating poorly compactable or moisture-sensitive drugs.

The influence of relative humidity on particulate interactions in carrier-based dry powder inhaler formulations.

An atomic force microscope (AFM) colloid probe technique has been used to investigate the effect of relative humidity (RH) on the adhesion properties of pharmaceutical powder surfaces. The adhesion between a model substrate, alpha-lactose monohydrate, and model particulate drugs, salbutamol sulphate and budesonide, was investigated between RHs of 15 and 75%. The surface topography of the model alpha-lactose monohydrate was produced by controlling the supersaturation conditions during crystal growth to produce sub-nanometre scale roughness. The adhesion interactions between lactose and drug probes of salbutamol sulphate and budesonide were shown to be significantly increased with each incremental rise in humidity. Capillary forces were significantly more dominant for the adhesion in the budesonide-lactose system up to 60% RH but were more dominant for salbutamol sulphate-lactose above 60% RH. These studies suggested that non-surface-specific capillary forces play a dominant role in the adhesion between drug and carrier, which may significantly reduce the deaggregation and dispersion properties of a dry powder formulation.

Chemical characterisation of sodium starch glycolate particles.

The internal and surface chemical compositions of three sodium starch glycolate (SSG) products, Explotab, Primojel and Vivastar P were studied using scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), time of flight secondary ion mass spectrometry (TOF-SIMS) and 23Na nuclear magnetic resonance spectroscopy (NMR). The surfaces of Explotab and Primojel contained very distinct features containing Na and Cl, however, Primojel also contained features which contained Na which may reflect the presence of Na glycolate and/or Na citrates. Vivastar P contained relatively few surface Cl containing features. Analysis of cross-sections of the particles showed that Na appeared to be uniformly distributed throughout the particles of all the products. Additionally, there was a significant concentration of Cl in the periphery of Explotab and Primojel. In the case of Vivastar P, significant levels of Na and Cl were detected in the internal regions of the particles which, together with 23Na NMR, suggests that NaCl is uniformly distributed within Vivastar P. 23Na NMR also suggested that the ratio of organic Na to NaCl was considerably lower in Vivastar P than Primojel and Explotab. Overall, even though all these three products satisfy the pharmacopeial descriptions of SSG, these studies suggest that Primojel and Explotab exhibit different chemical compositions to Vivastar P. Since the three products studied are reported to be prepared from potato starch, the apparent differences in chemical composition probably reflect the different manufacturing processes used, however, batch to batch variations may account for some of the subtle differences.

Altered expression and localization of PKC eta in human breast tumors.

Protein kinase C (PKC) eta is a PKC isoform whose upregulation is associated with differentiation in many epithelial tissues, including the rat mammary gland. The purpose of this study was to examine whether PKC eta is altered, in expression or localization, in human breast cancer. Paraffin sections of 49 in situ breast lesions, 29 invasive breast tumors, and nine normal breast biopsies were examined for PKC eta expression by immunohistochemistry. Adjacent regions of normal epithelium, and in situ lesions that were present adjacent to invasive lesions were also analyzed. In normal epithelium, regardless of the presence of adjacent in situ or invasive lesions, PKC eta was present in the cytoplasm of the luminal epithelium, and increased in areas of normal lobular development, similar to normal rat mammary gland. PKC eta staining intensity was homogeneous in normal lobules, but heterogeneous in in situ and invasive lesions, being focally increased in cells with aberrant nuclear morphology. In situ lesions were similar to adjacent normal epithelium in average staining intensity, regardless of whether invasion was also present. However, the invasive lesions themselves were significantly decreased in staining intensity compared to adjacent in situ lesions. In addition, 75% of invasive breast cancer lesions showed decreased staining relative to adjacent normal epithelium, compared to 37% of in situ lesions. The invasive tumors which possessed high PKC eta staining were associated with positive lymph node status. These results demonstrate that quantitative and qualitative alterations in PKC eta occur in human breast cancers.

Directional bonding in compacted microcrystalline cellulose.

The mechanical properties of compacts of microcrystalline cellulose (MCC) and silicified microcrystalline cellulose (SMCC) were evaluated by tensile testing, diametric compression testing, and compression testing. For tensile and compression testing, cubic specimens were carefully machined from MCC and SMCC compacts, and the tensile and compression strengths were evaluated both normal and parallel to the compaction direction. The cubic tensile strengths were compared to values obtained from the diametric compression test. The results obtained using the diametric compression test suggested compacts of SMCC exhibit greater strength than those of MCC. In addition, the cubes machined from compacts of MCC and SMCC exhibited directional strength; the direction normal to the compaction direction display ed the greater tensile strength, and the parallel direction had greater compression strength. The diametric compression test afforded strength values with reduced spread compared to the values collected from the cubic tensile test, suggesting that the errors involved in collecting diametric compression test data of compacts are less than those for the cubic tensile test. Analysis of the cubes using X-ray diffraction (XRD) suggested that they display directional structural anisotropy, with the direction normal to the compaction direction being more crystalline than the parallel direction. However, it is not clear whether the difference in the directional strength is solely a consequence of the increased crystallinity or a culmination of crystallographic and mechanical keying effects.

Accuracy of sentinel node biopsy in predicting nodal status in patients with breast carcinoma.

BACKGROUND AND OBJECTIVES: While sentinel lymph node biopsy is considered by many to have replaced axillary node dissection in the management of breast cancer, concerns remain regarding false-negative results. METHODS: To investigate the accuracy of sentinel node biopsy, we reexamined all sentinel and nonsentinel nodes with multilevel sectioning and immunohistochemical staining in 42 consecutive cases of breast cancer in which sentinel node biopsy was performed and followed by axillary dissection. RESULTS: By routine hematoxylin and eosin (H&E) staining, 34% of patients were found to be node positive, with no cases of false-negative sentinel node biopsy. Reevaluation of 775 negative sentinel and nonsentinel nodes with an additional two levels and immunohistochemistry identified three "node-negative" patients who had micrometastases in the sentinel node, increasing detection in 8% of cases. More important, is the fact however, that there were no cases where additional sections and immunohistochemistry identified metastases in nonsentinel nodes that had bypassed the sentinel node. The accuracy of the sentinel node in predicting the nodal status was 100%. CONCLUSIONS: Cytokeratin immunohistochemistry will identify more patients with nodal micrometastases; however, it was unable to identify any cases where micrometastases were present in nonsentinel nodes when the sentinel node was negative. The status of the sentinel node accurately identifies the status of the axillary basin.

Is MUGA scan necessary in patients with low-risk breast cancer before doxorubicin-based adjuvant therapy? Multiple gated acquisition.

Doxorubicin-based chemotherapy in the adjuvant treatment of breast cancer has become standard. Use of doxorubicin is limited by cardiac dysfunction; however, the incidence is dramatically reduced by limiting the dose to less than 550 mg/m(2). Although the cumulative dose in breast cancer is typically 240 mg/m(2), multiple gated acquisition (MUGA) scans are still recommended for determining cardiac functional status in these patients. To examine the need for this practice, we reviewed 296 patients who underwent surgery for breast cancer at Roswell Park Cancer Institute between July 1997 and December 1998. Fifty-nine of 95 (62%) patients receiving doxorubicin-based regimens, and 3 of 39 (7%) receiving nondoxorubicin regimens had pretreatment MUGA scans. The MUGA scans showed normal results in 58 patients and low-normal in 4 (6.5%), with no wall motion abnormalities encountered. There were no cases where doxorubicin was not used because of an abnormal MUGA scan. There were no cardiac complications in the 59 women who received doxorubicin-based chemotherapy. MUGA will screen out few, if any, women under consideration for doxorubicin-based adjuvant therapy; the decision to avoid doxorubicin can be made based on age and preexisting comorbidity. Guidelines recommending routine use of MUGA before the administration of doxorubicin for adjuvant therapy for breast cancer should be reconsidered.

Intraoperative pathologic evaluation of a breast cancer sentinel lymph node biopsy as a determinant for synchronous axillary lymph node dissection.

BACKGROUND: Intraoperative pathologic evaluation of a breast cancer sentinel lymph node (SLN) biopsy permits synchronous axillary lymph node dissection (ALND), but frozen section is time consuming and potentially inaccurate. This study evaluated intraoperative gross examination and touch prep analysis (TPA) of a breast cancer SLN biopsy as determinants for synchronous ALND. METHODS: Intraoperative gross examination/TPA were performed on the SLN of consecutive breast cancer patients from 1997 to 2000. Patients with an intraoperative "positive" SLN underwent synchronous ALND. Intraoperative results were compared with the final pathology. RESULTS: Thirty-seven of 150 patients had a positive SLN on final pathology. Intraoperative gross examination/TPA identified 54% (20 of 37) of these patients. All intraoperative "positive" patients underwent synchronous ALND. Of 17 "false-negative" findings, 53% (9 of 17) had micrometastatic disease. There were no "false-positive" results. Overall sensitivity and specificity were 54% and 100%, respectively. CONCLUSIONS: Gross examination/TPA are simple, rapid techniques for the intraoperative evaluation of a breast cancer SLN. As there were no false-positive results, the rationale behind SLN biopsy was preserved. These techniques permitted synchronous ALND in over half of all patients with a positive SLN. This represents a potential benefit to the patient by eliminating a second hospitalization for delayed ALND.

Downregulation of gelsolin correlates with the progression to breast carcinoma.

The actin cytoskeleton underlies several normal cellular functions and is deranged during carcinogenesis. Gelsolin, a multifunctional actin-binding protein, is downregulated in several types of tumors and its abnormal expression is one of the most common defects noted in invasive breast carcinoma (ICA). This study utilizes immunohistochemistry to examine the expression of gelsolin in 95 ICA, 59 ductal carcinoma in situ (DCIS) and 36 benign lesions, including 17 atypical ductal hyperplasia (ADH). Cytoplasmic staining was scored as positive, reduced or negative. Gelsolin expression was then correlated with patient's age, tumor size, histologic grade and lymph node status. All unremarkable breast biopsies, 88% of ADH, 44% of DCIS and 28% of ICA were positive for gelsolin. This represents a significant difference among the groups (p = < 0.0001) and the trend towards reduced gelsolin with the progression to ICA is significantly linear (p = < 0.0001). For invasive carcinoma, patients older than 44 years were significantly more likely to have decreased expression of gelsolin than patients 44 years old and younger (p = 0.007). Bivariate analysis showed no correlation of gelsolin expression with lymph node status (p = 0.62), tumor size (p = 0.10), histologic grade (p = 0.42), estrogen receptor status (p = 1.0) or other clinicopathologic parameters. In clinical follow-up, there were 18 breast tumor related deaths within a median follow-up time of 4.2 years. Survival analysis indicated that the level of gelsolin expression may be associated with survival (p = 0.06). In summary, the frequency of gelsolin deficiency increases significantly with progression from ADH to DCIS to ICA. Additionally, gelsolin expression may be an independent marker of prognosis.

Measuring and predicting surgeons' practice styles for breast cancer treatment in older women.

BACKGROUND: Few measures exist to assess physicians' practice style, and there are few data on physicians' practice styles and patterns of care. OBJECTIVES: To use clinical vignettes to measure surgeons' "propensity" for local treatments for early-stage breast cancer and to describe factors associated with propensity. RESEARCH DESIGN AND SUBJECTS: A cross-sectional mailed survey with telephone follow-up of a random sample of 1,000 surgeons treating Medicare beneficiaries in fee-for-service settings. MEASURES: Outcome measures include treatment propensity, self-reported practice, and actual treatment received by the surgeons' patients. RESULTS: Propensities were significantly associated with actual treatment, controlling for covariates. Area Medicare fees were the strongest predictor of propensity, followed by region, attitudes, volume, and gender. For instance, after other factors were considered, surgeons practicing in areas with the highest breast-conserving surgery (BCS) fees were 8.61 (95% CI 2.26-32.73) times more likely to have a BCS propensity than surgeons in areas with the lowest fees. Surgeons with the strongest beliefs in patient participation in treatment decisions were nearly 6 times (95% CI 1.67-20.84) more likely to have a BCS propensity than surgeons with the lowest such beliefs, controlling for covariates. Male surgeons were also independently more likely to have a mastectomy propensity than female surgeons. CONCLUSIONS: Surgeons' propensities explain some of the observed variations in breast cancer treatment patterns among older women. Standardized scenarios provide a practical method to measure practice style and could be used to evaluate physician contributions to shared decision making, practice patterns, costs and outcomes, and adherence to guidelines.

Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology.

OBJECTIVE: To determine indications for the use of postmastectomy radiotherapy (PMRT) for patients with invasive breast cancer with involved axillary lymph nodes or locally advanced disease who receive systemic therapy. These guidelines are intended for use in the care of patients outside of clinical trials. POTENTIAL INTERVENTION: The benefits and risks of PMRT in such patients, as well as subgroups of these patients, were considered. The details of the PMRT technique were also evaluated. OUTCOMES: The outcomes considered included freedom from local-regional recurrence, survival (disease-free and overall), and long-term toxicity. EVIDENCE: An expert multidisciplinary panel reviewed pertinent information from the published literature through July 2000; certain investigators were contacted for more recent and, in some cases, unpublished information. A computerized search was performed of MEDLINE data; directed searches based on the bibliographies of primary articles were also performed. VALUES: Levels of evidence and guideline grades were assigned by the Panel using standard criteria. A "recommendation" was made when level I or II evidence was available and there was consensus as to its meaning. A "suggestion" was made based on level III, IV, or V evidence and there was consensus as to its meaning. Areas of clinical importance were pointed out where guidelines could not be formulated due to insufficient evidence or lack of consensus. RECOMMENDATIONS: The recommendations, suggestions, and expert opinions of the Panel are described in this article. VALIDATION: Seven outside reviewers, the American Society of Clinical Oncology (ASCO) Health Services Research Committee members, and the ASCO Board of Directors reviewed this document.