Lung SBRT credentialing in the Canadian OCOG-LUSTRE randomized trial.

Purpose: To report on the Stereotactic Body Radiation Therapy (SBRT) credentialing experience during the Phase III Ontario Clinical Oncology Group (OCOG) LUSTRE trial for stage I non-small cell lung cancer. Methods: Three credentialing requirements were required in this process: (a) An institutional technical survey; (b) IROC (Imaging and Radiation Oncology Core) thoracic phantom end-to-end test; and (c) Contouring and completion of standardized test cases using SBRT for one central and one peripheral lung cancer, compared against the host institution as the standard. The main hypotheses were that unacceptable variation would exist particularly in OAR definition across all centres, and that institutions with limited experience in SBRT would be more likely to violate per-protocol guidelines. Results: Fifteen Canadian centres participated of which 8 were new, and 7 were previously established (≥2 years SBRT experience), and all successfully completed surveys and IROC phantom testing. Of 30 SBRT test plans, 10 required replanning due to major deviations, with no differences in violations between new and established centres (p = 0.61). Mean contouring errors were highest for brachial plexus in the central (C) case (12.55 ± 6.62 mm), and vessels in the peripheral (P) case (13.01 ± 12.55 mm), with the proximal bronchial tree (PBT) (2.82 ± 0.78 C, 3.27 ± 1.06 P) as another variable structure. Mean dice coefficients were lowest for plexus (0.37 ± 0.2 C, 0.37 ± 0.14 P), PBT (0.77 ± 0.06 C, 0.75 ± 0.09 P), vessels (0.69 ± 0.29 C, 0.64 ± 0.31 P), and esophagus (0.74 ± 0.04 C, 0.76 ± 0.04 P). All plans passed per-protocol planning target volume (PTV) coverage and maximum/volumetric organs-at-risk constraints, although variations existed in dose gradients within and outside the target. Conclusions: Clear differences exist in both contouring and planning with lung SBRT, regardless of centre experience. Such an exercise is important for studies that rely on high precision radiotherapy, and to ensure that implications on trial quality and outcomes are as optimal as possible.

Identification of a novel IL-5 signaling pathway in chronic pancreatitis and crosstalk with pancreatic tumor cells.

BACKGROUND: While inflammation is associated with pancreatic cancer, the underlying mechanisms leading to cancer initiation are still being delineated. Eosinophils may promote or inhibit tumor growth, although the specific role in pancreatic cancer has yet to be determined. Eosinophil-supporting cytokine interleukin-5 and receptor are likely to have a role, but the significance in the pancreatic cancer microenvironment is unknown. METHODS: Genetically engineered Akt1Myr/KRasG12D and KRasG12D mice were used to model changes induced by chronic inflammation. Tissue samples were collected to analyze the tumor microenvironment and infiltration of immune cells, whereas serum was collected to analyze cytokine and amylase activity in the inflammatory model. The expression of IL-5R and the effects of IL-5 were analyzed in human and murine tumor cells. RESULTS: Compound Akt1Myr/KRasG12D mice, compared to single KRasG12D or Akt1Myr mice, exhibited increased tissue damage after repeat inductions of inflammation, and had accelerated tumor development and metastasis. M2 macrophages and newly identified eosinophils co-localized with fibrotic regions rather than infiltrating into tumors, consistent with immune cell privilege. The majority of eosinophils found in the pancreas of Akt1Myr/KRasG12D mice with chronic inflammation lacked the cytotoxic NKG2D marker. IL-5 expression was upregulated in pancreatic cells in response to inflammation, and then diminished in advanced lesions. Although not previously described in pancreatic tumors, IL-5Rα was increased during mouse pancreatic tumor progression and expressed in human pancreatic ductal adenocarcinomas (7 of 7 by immunohistochemistry). IL-5 stimulated tumor cell migration and activation through STAT5 signaling, thereby suggesting an unreported tumor-promoting role for IL-5Rα in pancreatic cancer. CONCLUSIONS: Chronic inflammation induces increased pancreatic cancer progression and immune cells such as eosinophils are attracted to areas of fibrosis. Results suggest that IL-5 in the pancreatic compartment stimulates increased IL-5Rα on ductal tumor cells to increase pancreatic tumor motility. Collectively, IL-5/IL-5Rα signaling in the mouse and human pancreatic tumors microenvironment is a novel mechanism to facilitate tumor progression. Additional file 1: Video Abstract.

Canadian Phase III Randomized Trial of Stereotactic Body Radiotherapy Versus Conventionally Hypofractionated Radiotherapy for Stage I, Medically Inoperable Non-Small-Cell Lung Cancer - Rationale and Protocol Design for the Ontario Clinical Oncology Group (OCOG)-LUSTRE Trial.

We describe a Canadian phase III randomized controlled trial of stereotactic body radiotherapy (SBRT) versus conventionally hypofractionated radiotherapy (CRT) for the treatment of stage I medically inoperable non-small-cell lung cancer (OCOG-LUSTRE Trial). Eligible patients are randomized in a 2:1 fashion to either SBRT (48 Gy in 4 fractions for peripherally located lesions; 60 Gy in 8 fractions for centrally located lesions) or CRT (60 Gy in 15 fractions). The primary outcome of the study is 3-year local control, which we hypothesize will improve from 75% with CRT to 87.5% with SBRT. With 85% power to detect a difference of this magnitude (hazard ratio = 0.46), a 2-sided α = 0.05 and a 2:1 randomization, we require a sample size of 324 patients (216 SBRT, 108 CRT). Important secondary outcomes include overall survival, disease-free survival, toxicity, radiation-related treatment death, quality of life, and cost-effectiveness. A robust radiation therapy quality assurance program has been established to assure consistent and high quality SBRT and CRT delivery. Despite widespread interest and adoption of SBRT, there still remains a concern regarding long-term control and risks of toxicity (particularly in patients with centrally located lesions). The OCOG-LUSTRE study is the only randomized phase III trial testing SBRT in a medically inoperable population, and the results of this trial will attempt to prove that the benefits of SBRT outweigh the potential risks.

Cortical innervation of the hypoglossal nucleus in the non-human primate (Macaca mulatta).

The corticobulbar projection to the hypoglossal nucleus was studied from the frontal, parietal, cingulate, and insular cortices in the rhesus monkey by using high-resolution anterograde tracers and stereology. The hypoglossal nucleus received bilateral input from the face/head region of the primary (M1), ventrolateral pre- (LPMCv), supplementary (M2), rostral cingulate (M3), and caudal cingulate (M4) motor cortices. Additional bilateral corticohypoglossal projections were found from the dorsolateral premotor cortex (LPMCd), ventrolateral proisocortical motor area (ProM), ventrolateral primary somatosensory cortex (S1), rostral insula, and pregenual region of the anterior cingulate gyrus (areas 24/32). Dense terminal projections arose from the ventral region of M1, and moderate projections from LPMCv and rostral part of M2, with considerably fewer hypoglossal projections arising from the other cortical regions. These findings demonstrate that extensive regions of the non-human primate cerebral cortex innervate the hypoglossal nucleus. The widespread and bilateral nature of this corticobulbar connection suggests recovery of tongue movement after cortical injury that compromises a subset of these areas, may occur from spared corticohypoglossal projection areas located on the lateral, as well as medial surfaces of both hemispheres. Since functional imaging studies have shown that homologous cortical areas are activated in humans during tongue movement tasks, these corticobulbar projections may exist in the human brain.

The role of the medial prefrontal cortex in the acquisition, retention, and reversal of a tactile visuospatial conditional discrimination task.

The medial prefrontal cortex (mPFC) is responsible for executive functions such as abstract rule coding, strategy switching, and behavioral flexibility; however, there is some debate regarding the extent to which mPFC is involved in reversal learning, especially in complex multisensory tasks such as conditional discrimination. Therefore, we investigated the effects of mPFC inactivation on the acquisition, retention, and reversal of a visuospatial conditional discrimination (CD) task. In experiment 1, muscimol was infused through bilateral cannulae on days 1, 2, and 3 to test the effects of mPFC inactivation on task acquisition and days 19, 20, and 21 to test the effects on retention of the task. For experiment 2, rats were trained on the CD task for 21 days with no infusions given, after which the reward contingency was reversed, with infusions given during the first six days of reversal. The results of experiment 1 showed that the muscimol and saline groups did not differ on acquisition or retention. However, experiment 2 showed that the muscimol group displayed significantly more performance errors than the control group during reversal. Compared to the control group, the muscimol group also showed a decreased tendency to use a side-bias strategy during the intermediate stages of reversal. The failure of the muscimol group to exhibit a side bias suggests that the mPFC is necessary for sampling strategies necessary for the reversal of a visuospatial CD task.

Spatial representations in dorsal hippocampal neurons during a tactile-visual conditional discrimination task.

Trajectory-dependent coding in dorsal CA1 of hippocampus has been evident in various spatial memory tasks aiming to model episodic memory. Hippocampal neurons are considered to be trajectory-dependent if the neuron has a place field located on an overlapping segment of two trajectories and exhibits a reliable difference in firing rate between the two trajectories. It is unclear whether trajectory-dependent coding in hippocampus is a mechanism used by the rat to solve spatial memory tasks. A first step in answering this question is to compare results between studies using tasks that require spatial working memory and those that do not. We recorded single units from dorsal CA1 of hippocampus during performance of a discrete-trial, tactile-visual conditional discrimination (CD) task in a T-maze. In this task, removable floor inserts that differ in texture and appearance cue the rat to visit either the left or right goal arm to receive a food reward. Our goal was to assess whether trajectory coding would be evident in the CD task. Our results show that trajectory coding was rare in the CD task, with only 12 of 71 cells with place fields on the maze stem showing a significant firing rate difference between left and right trials. For comparison, we recorded from dorsal CA1 during the acquisition and performance of a continuous spatial alternation task identical to that used in previous studies and found a proportion of trajectory coding neurons similar to what has been previously reported. Our data suggest that trajectory coding is not a universal mechanism used by the hippocampus to disambiguate similar trajectories, and instead may be more likely to appear in tasks that require the animal to retrieve information about a past trajectory, particularly in tasks that are continuous rather than discrete in nature.

Volumetric effects of motor cortex injury on recovery of ipsilesional dexterous movements.

Damage to the motor cortex of one hemisphere has classically been associated with contralateral upper limb paresis, but recent patient studies have identified deficits in both upper limbs. In non-human primates, we tested the hypothesis that the severity of ipsilesional upper limb motor impairment in the early post-injury phase depends on the volume of gray and white matter damage of the motor areas of the frontal lobe. We also postulated that substantial recovery would accompany minimal task practice and that ipsilesional limb recovery would be correlated with recovery of the contralesional limb. Gross (reaching) and fine hand motor functions were assessed for 3-12 months post-injury using two motor tests. Volumes of white and gray matter lesions were assessed using quantitative histology. Early changes in post-lesion motor performance were inversely correlated with white matter lesion volume indicating that larger lesions produced greater decreases in ipsilesional hand movement control. All monkeys showed improvements in ipsilesional hand motor skill during the post-lesion period, with reaching skill improvements being positively correlated with total lesion volume indicating that larger lesions were associated with greater ipsilesional motor skill recovery. We suggest that reduced trans-callosal inhibition from the lesioned hemisphere may play a role in the observed skill improvements. Our findings show that significant ipsilesional hand motor recovery is likely to accompany injury limited to frontal motor areas. In humans, more pronounced ipsilesional motor deficits that invariably develop after stroke may, in part, be a consequence of more extensive subcortical white and gray matter damage.

Positron emission tomography-computed tomography compared with invasive mediastinal staging in non-small cell lung cancer: results of mediastinal staging in the early lung positron emission tomography trial.

INTRODUCTION: Patients with non-small cell lung cancer (NSCLC) require careful preoperative staging to define resectability for potential cure. Fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG PET-CT) is widely used to stage NSCLC. If the mediastinum is positive on PET-CT examination, some practitioners conclude that the patient is inoperable and refer the patient for nonsurgical treatment. METHODS: In this analysis of a previously reported trial comparing PET-CT with conventional imaging in the diagnostic work-up of patients with clinical stage I, II, or IIIA NSCLC, we determined the accuracy of PET-CT in mediastinal staging compared with invasive mediastinal staging either by mediastinoscopy alone or by mediastinoscopy combined with thoracotomy. RESULTS: All 149 patients had mediastinal nodal staging at mediastinoscopy alone (14), thoracotomy alone (64), or both (71). The sensitivity of PET-CT was 70% (95% confidence interval [CI], 48-85%), and specificity was 94% (95% CI, 88-97%). Of 22 patients with a PET-CT interpreted as positive for mediastinal nodes, 8 did not have tumor. The positive predictive value and negative predictive value were 64% (95% CI, 43-80%) and 95% (95% CI, 90-98%), respectively. Based on PET-CT alone, eight patients would have been denied potentially curative surgery if the mediastinal abnormalities detected by PET-CT had not been evaluated with an invasive mediastinal procedure. CONCLUSIONS: PET-CT assessment of the mediastinum is associated with a clinically relevant false-positive rate. Our study confirms the need for pathologic confirmation of mediastinal lymph node abnormalities detected by PET-CT.

Minimal forced use without constraint stimulates spontaneous use of the impaired upper extremity following motor cortex injury.

The purpose of this study was to determine if recovery of neurologically impaired hand function following isolated motor cortex injury would occur without constraint of the non-impaired limb, and without daily forced use of the impaired limb. Nine monkeys (Macaca mulatta) received neurosurgical lesions of various extents to arm representations of motor cortex in the hemisphere contralateral to the preferred hand. After the lesion, no physical constraints were placed on the ipsilesional arm/hand and motor testing was carried out weekly with a maximum of 40 attempts in two fine motor tasks that required use of the contralesional hand for successful food acquisition. These motor tests were the only "forced use" of the contralesional hand. We also tested regularly for spontaneous use of the contralesional hand in a fine motor task in which either hand could be used for successful performance. This minimal intervention was sufficient to induce recovery of the contralesional hand to such a functional level that eight of the monkeys chose to use that hand on some trials when either hand could be used. Percentage use of the contralesional hand (in the task when either hand could be used) varied considerably among monkeys and was not related to lesion volume or recovery of motor skill. These data demonstrate a remarkable capacity for recovery of spontaneous use of the impaired hand following localized frontal lobe lesions. Clinically, these observations underscore the importance of therapeutic intervention to inhibit the induction of the learned nonuse phenomenon after neurological injury.

Positron emission tomography in staging early lung cancer: a randomized trial.

BACKGROUND: Among patients with early-stage non-small cell lung cancer (NSCLC), preoperative imaging tests are important in defining surgical candidates. OBJECTIVE: To assess whether whole-body positron emission tomography and computed tomography (PET-CT) plus cranial imaging correctly upstages cancer in more patients with NSCLC than does conventional staging plus cranial imaging. DESIGN: Randomized clinical trial with recruitment from June 2004 to August 2007. The centralized, computer-generated, variable block size randomization scheme was stratified by treatment center and cancer stage. Participants, health care providers, and outcome assessors were not blinded to imaging modality assignment. SETTING: 8 hospitals and 5 PET-CT centers in academic institutions. PATIENTS: Eligible patients were older than 18 years; had histologic or cytologic proof of stage I, II, or IIIA NSCLC on the basis of chest radiography and thoracic CT; and had a tumor considered to be resectable. INTERVENTION: PET-CT or conventional staging (abdominal CT and bone scan). All patients also had cranial imaging using CT or magnetic resonance imaging. MEASUREMENTS: The primary outcome was correct upstaging, thereby avoiding stage-inappropriate surgery. Secondary outcomes were incorrect upstaging and incorrect understaging. RESULTS: 170 patients were assigned to PET-CT and 167 to conventional staging. Eight patients (3 who had PET-CT and 5 who had conventional staging) did not have planned surgery. Disease was correctly upstaged in 23 of 167 PET-CT recipients and 11 of 162 conventional staging recipients (13.8% vs. 6.8%; difference, 7.0 percentage points [95% CI, 0.3 to 13.7 percentage points]), thereby sparing these patients from surgery. Disease was incorrectly upstaged in 8 PET-CT recipients and 1 conventional staging recipient (4.8% vs. 0.6%; difference, 4.2 percentage points [CI, 0.5 to 8.6 percentage points]), and it was incorrectly understaged in 25 and 48 patients, respectively (14.9% vs. 29.6%; difference, 14.7 percentage points [CI, 5.7 to 23.4 percentage points]). At 3 years, 52 patients who had PET-CT and 57 patients who had conventional staging had died. LIMITATION: The relatively small sample and the fact that some patients did not have planned surgery limited the ability to determine precise differences in clinical outcomes that were attributable to testing strategies. CONCLUSION: Preoperative staging with PET-CT and cranial imaging identifies more patients with mediastinal and extrathoracic disease than conventional staging, thereby sparing more patients from stage-inappropriate surgery, but the strategy also incorrectly upstaged disease in more patients.

Assessing the quality of colorectal cancer care: do we have appropriate quality measures? (A systematic review of literature).

RATIONALE, AIMS AND OBJECTIVES: The burden of illness from colorectal cancer (CRC) can be reduced by improving the quality of care. Identifying appropriate quality measures is the first step in this direction. We identified process measures currently available to assess the quality of diagnosis and management of CRC. We also evaluated the extent to which these measures are ready to be implemented in clinical practice, and identified areas for future research. METHODS: We searched MEDLINE, Cochrane Database of Systematic Reviews, and relevant grey literature. We identified 3771 abstracts and reviewed 74 articles that included quality measures for diagnosis or management of CRC. Measures from traditional quality improvement literature, and from epidemiological and other studies that included quality measures as part of their research agenda, were considered. In addition, we devised a summary rating scale (IST) to appraise the extent of a measure's importance and usability, scientific acceptability and extent of testing. RESULTS: The coverage of general process measures in CRC is extensive. Most measures are important, but need to be developed and field-tested. The best available measures relate to pathology and chemotherapy. No measures are available for assessing quality of management of stage IV rectal cancer and hepatic metastasis; chemotherapy for stage II colon cancer; and procedure notes. CONCLUSIONS: There is an urgent need to refine existing measures and to develop scientifically accurate quality measures for a comprehensive assessment of the quality of CRC care. The role of the federal government and professional societies is critical in pursuing this goal.

Review of evidence for genetic testing for CYP450 polymorphisms in management of patients with nonpsychotic depression with selective serotonin reuptake inhibitors.

PURPOSE: Cytochrome P450 (CYP450) enzymes metabolize selective serotonin reuptake inhibitor (SSRI) drugs used in treatment of depression. Variants in these genes may impact treatment efficacy and tolerability. The purpose of this study was 2-fold: to systematically review the literature for evidence supporting CYP450 genotyping to guide SSRI treatment for major depression, and, where evidence is inadequate, to suggest future research. METHODS: We searched MEDLINE(R) and other databases for studies addressing five key questions suggested by the Evaluation of Genomic Applications in Practice and Prevention Working Group. Eligibility criteria were defined, and studies were reviewed independently by paired researchers. A conceptual model was developed to guide future research. RESULTS: Review of 1200 abstracts led to the final inclusion of 37 articles. The evidence indicates relatively high analytic sensitivity and specificity of tests detecting a subset of polymorphisms of CYP2D6, 2C19, 2C8, 2C9, and 1A1. We found marginal evidence regarding a clinical association between CYP450 variants and SSRI metabolism, efficacy, and tolerability in the treatment of depression. CONCLUSIONS: Current evidence does not support the use of CYP450 genotyping to guide SSRI treatment of patients with depression. Studies are proposed that will effectively guide decision-making in the area of CYP450 testing in depression, and genetic testing more generally.

Testing for cytochrome P450 polymorphisms in adults with non-psychotic depression treated with selective serotonin reuptake inhibitors (SSRIs).

OBJECTIVES: To determine if testing for cytochrome P450 (CYP450) polymorphisms in adults entering selective serotonin reuptake inhibitor (SSRI) treatment for non-psychotic depression leads to improvement in outcomes, or if testing results are useful in medical, personal, or public health decisionmaking. DATA SOURCES: We searched MEDLINE, the Cochrane Database of Abstracts of Reviews of Effects, PsychInfo, HealthSTAR, and CINAHL, and reviewed the reference lists of included articles and relevant review articles and meta-analyses for eligible studies. We also included documents from the U.S. Food and Drug Administration (FDA) that could be publicly accessed. REVIEW METHODS: We developed an analytic framework and identified key questions to guide the review process. Project-specific inclusion/exclusion criteria were also developed and were used by paired researchers independently to review both abstracts and full-text articles; both researchers were required to agree on inclusion status at the full-text stage. Abstractors evaluated each included article for factors affecting internal and external validity. RESULTS: A review of 1,200 abstracts led to the final inclusion of 37 articles. The evidence indicates the existence of tests with high sensitivity and specificity for detecting only a few of the more common known polymorphisms of 2D6, 2C19, 2C8, 2C9, and 1A1. There is mixed evidence regarding the association between CYP450 genotypes and SSRI metabolism, efficacy, and tolerability in the treatment of depression, mainly from a series of heterogeneous studies in small samples. There are no data regarding: (a) if testing for CYP450 polymorphisms in adults entering SSRI treatment for non-psychotic depression leads to improvement in outcomes versus not testing, or if testing results are useful in medical, personal, or public health decisionmaking; (b) if CYP450 testing influences depression management decisions by patients and providers in ways that could improve or worsen outcomes; or (c) if there are direct or indirect harms associated with testing for CYP450 polymorphisms or with subsequent management options. CONCLUSIONS: There is a paucity of good-quality data addressing the questions of whether testing for CYP450 polymorphisms in adults entering SSRI treatment for non-psychotic depression leads to improvement in outcomes, or whether testing results are useful in medical, personal, or public health decisionmaking.

Quality measures for the use of adjuvant chemotherapy and radiation therapy in patients with colorectal cancer: a systematic review.

BACKGROUND: Chemotherapy (CT) and radiation therapy (RT) are essential components of adjuvant (preoperative or postoperative) therapy for many patients with colorectal cancer (CRC); however, quality measures (QMs) of these critical aspects of CRC treatment have not been characterized well. Therefore, the authors conducted a systematic review of the literature to determine the available QMs for adjuvant CT and RT in patients with CRC and rated their usefulness for assessing the delivery of quality care. METHODS: The MEDLINE and Cochrane data bases were searched for all publications that contained potential/actual QMs pertaining to adjuvant therapy for CRC. Identified QMs were rated by using criteria developed by the National Quality Forum. RESULTS: Thirty-two articles met the established inclusion/exclusion criteria. Those 32 articles contained 12 potential or actual QMs, 6 of which had major flaws that limited their applicability. The most useful QMs identified were 1) the percentage of patients with AJCC Stage III colon cancer who received postoperative CT and 2) the percentage of patients with Stage II or III rectal cancer who received chemoradiotherapy. CONCLUSIONS: To the authors' knowledge, very few QMs pertaining to adjuvant CT or RT for CRC have been published to date, and only half of those measures were rated as useful, acceptable, and valid in the current literature review. Future research should focus on refining existing QMs and on developing new QMs that target important leverage points with respect to the provision of adjuvant therapy for patients with CRC.

Genomic tests for ovarian cancer detection and management.

OBJECTIVES: To assess the evidence that the use of genomic tests for ovarian cancer screening, diagnosis, and treatment leads to improved outcomes. DATA SOURCES: PubMed and reference lists of recent reviews. REVIEW METHODS: We evaluated tests for: (a) single gene products; (b) genetic variations affecting risk of ovarian cancer; (c) gene expression; and (d) proteomics. For tests covered in recent evidence reports (cancer antigen 125 [CA-125] and breast cancer genes 1 and 2 [BRCA1/2]), we added studies published subsequent to the reports. We sought evidence on: (a) the analytic performance of tests in clinical laboratories; (b) the sensitivity and specificity of tests in different patient populations; (c) the clinical impact of testing in asymptomatic women, women with suspected ovarian cancer, and women with diagnosed ovarian cancer; (d) the harms of genomic testing; and (e) the impact of direct-to-consumer and direct-to-physician advertising on appropriate use of tests. We also constructed a computer simulation model to test the impact of different assumptions about ovarian cancer natural history on the relative effectiveness of different strategies. RESULTS: There are reasonable data on the clinical laboratory performance of most radioimmunoassays, but the majority of the data on other genomic tests comes from research laboratories. Genomic test sensitivity/specificity estimates are limited by small sample sizes, spectrum bias, and unrealistically large prevalences of ovarian cancer; in particular, estimates of positive predictive values derived from most of the studies are substantially higher than would be expected in most screening or diagnostic settings. We found no evidence relevant to the question of the impact of genomic tests on health outcomes in asymptomatic women. Although there is a relatively large literature on the association of test results and various clinical outcomes, the clinical utility of changing management based on these results has not been evaluated. We found no evidence that genomic tests for ovarian cancer have unique harms beyond those common to other tests for genetic susceptibility or other tests used in screening, diagnosis, and management of ovarian cancer. Studies of a direct-to-consumer campaign for BRCA1/2 testing suggest increased utilization, but the effect on "appropriateness" was unclear. Model simulations suggest that annual screening, even with a highly sensitive test, will not reduce ovarian cancer mortality by more than 50 percent; frequent screening has a very low positive predictive value, even with a highly specific test. CONCLUSIONS: Although research remains promising, adaptation of genomic tests into clinical practice must await appropriately designed and powered studies in relevant clinical settings.

Cancer care quality measures: diagnosis and treatment of colorectal cancer.

OBJECTIVES: To identify measures that are currently available to assess the quality of care provided to patients with colorectal cancer (CRC), and to assess the extent to which these measures have been developed and tested. DATA SOURCES: Published and unpublished measures identified through a computerized search of English-language citations in MEDLINE (1966-January 2005), the Cochrane Database of Systematic Reviews, and the National Guideline Clearinghouse; through review of reference lists contained in seed articles, all included articles, and relevant review articles; and through searches of the grey literature (institutional or government reports, professional society documents, research papers, and other literature, in print or electronic format, not controlled by commercial publishing interests). Sources for grey literature included professional organization websites and the Internet. REVIEW METHODS: Measures were selected by reviewers according to standardized criteria relating to each question, and were then rated according to their importance and usability, scientific acceptability, and extent of testing; each domain was rated from 1 (poor) to 5 (ideal). RESULTS: We identified a number of well-developed and well-tested CRC-related quality-of-care measures, both general process-of-care measures (on a broader scale) and technical measures (pertaining to specific details of a procedure). At least some process measures are available for diagnostic imaging, staging, surgical therapy, adjuvant chemotherapy, adjuvant radiation therapy, and colonoscopic surveillance. Various technical measures were identified for quality of colonoscopy (e.g., cecal intubation rate, complications) and staging (adequate lymph node retrieval and evaluation). These technical measures were guideline-based and well developed, but less well tested, and the linkage between them and patient outcomes, although intuitive, was not always explicitly provided. For some elements of the care pathway, such as operative reports and chemotherapy reports, no technical measures were found. CONCLUSIONS: Some general process measures have a stronger evidence base than others. Those based on guidelines have the strongest evidence base; those derived from basic first principles supported by some research findings are relatively weaker, but are often sufficient for the task at hand. A consistent source of tension is the distinction between the clinically derived fine-tuning of the definition of a quality measure and the limitations of available data sources (which often do not contain sufficient information to act on such distinctions). Although some excellent technical measures were found, the overall development of technical measures seems less advanced than that of the general process measures.

Management of adnexal mass.

OBJECTIVES: To assess diagnostic strategies for distinguishing benign from malignant adnexal masses. DATA SOURCES: MEDLINE(R) and reference lists of recent reviews; discharge data from the Nationwide Inpatient Sample. REVIEW METHODS: The major diagnostic methods evaluated were bimanual pelvic examination, ultrasound (morphology and Doppler velocimetry), MRI, CT, FDG-PET, CA-125, and scoring systems that incorporated multiple clinical, laboratory, and radiologic findings. Meta-analysis using a random-effects model was used to estimate pooled sensitivity and specificity for discriminating benign from malignant. We reviewed evidence for followup strategies for masses considered benign, and for adverse outcomes of diagnostic surgery. We also reviewed published models of the natural history of ovarian cancer and compared the impact of assumptions about natural history on outcomes. RESULTS: The majority of studies did not describe whether patients presented with asymptomatic masses detected through screening or with symptoms. Prevalence of malignant masses in a U.S. postmenopausal screening population was approximately 0.1 percent, while benign masses were found in 0.8 to 1.8 percent of women. Pooled (a) sensitivity and (b) specificity were: bimanual exam (a) 0.45, (b) 0.90; ultrasound morphology scores (a) 0.86 to 0.91, (b) 0.68 to 0.83; Doppler resistive index (a) 0.72, (b) 0.90; pulsatility index (a) 0.80, (b) 0.73; maximum systolic velocity (a) 0.74, (b) 0.81; presence of vessels (a) 0.88, (b) 0.78; combined morphology and Doppler (a) 0.86, (b) 0.91; MRI (a) 0.91, (b) 0.88; CT (a) 0.90, (b) 0.75; FDG-PET (a) 0.67, (b) 0.79; and CA-125 (a) 0.78, (b) 0.78. Both sensitivity and specificity of CA-125 were better in postmenopausal than in premenopausal women. In modeled outcomes, combinations of imaging and CA-125 were both more sensitive and more specific than either alone. Performance of scoring systems in validation studies was consistently worse than in development studies; the highest demonstrated specificity observed was 0.91, with a concurrent sensitivity of 0.74. Evidence on followup strategies was sparse, although one large study provided good evidence for safely following unilocular cysts less than 10 cm in diameter. Overall complication rates in studies of surgically managed adnexal masses were low, but important clinical information was not reported. CONCLUSIONS: All diagnostic modalities showed trade-offs between sensitivity and specificity, but the available literature does not provide sufficient detail on relevant characteristics of study populations to allow confident estimation of the results of alternative diagnostic strategies. Although modeling studies may prove useful in evaluating diagnostic algorithms, further work is needed to explore the implications of uncertainty about the natural history of ovarian cancer.