Craig D. Shriver

Assessing semantic similarity measures for the characterization of human regulatory pathways

MOTIVATION Pathway modeling requires the integration of multiple data including prior knowledge. In this study, we quantitatively assess the application of Gene Ontology (GO)-derived similarity measures for the characterization of direct and indirect interactions within human regulatory pathways. The characterization would help the integration of prior pathway knowledge for the modeling. RESULTS Our analysis indicates information content-based measures outperform graph structure-based measures for stratifying protein interactions. Measures in terms of GO biological process and molecular function annotations can be used alone or together for the validation of protein interactions involved in the pathways. However, GO cellular component-derived measures may not have the ability to separate true positives from noise. Furthermore, we demonstrate that the functional similarity of proteins within known regulatory pathways decays rapidly as the path length between two proteins increases. Several logistic regression models are built to estimate the confidence of both direct and indirect interactions within a pathway, which may be used to score putative pathways inferred from a scaffold of molecular interactions.

Decision making on surgical palliation based on patient outcome data

BACKGROUND Strategies for the effective application of palliative procedures are infrequently standardized and incompletely understood. The effect on patient outcome as determined by elements such as resolution of chief complaints, quality of life, pain control, morbidity of therapy, and resource utilization should predominate decisions regarding surgical palliative care. METHODS Articles published between 1990 and 1996 on the surgical palliation of cancer were identified by a MEDLINE search and reviewed for designated parameters considered important for good palliative care. RESULTS A total of 348 citations were included. Entries considered these fundamental elements: cost (2%); pain control (12%); quality of life (17%); need to repeat the intervention (59%); morbidity and mortality (61 %); survival (64%); and physiologic response (69%). Established methods for quality of life and pain assessment were sporadically utilized. CONCLUSIONS In the current surgical literature, there is uncommon reporting of the range of data required to recommend sound palliative surgical choices.

Circulating MMP2 and MMP9 in breast cancer : Potential role in classification of patients into low risk, high risk, benign disease and breast cancer categories

Matrix metalloproteinase (MMP) 2 and 9 are involved in cancer invasion and metastasis, and increased levels occur in serum and plasma of breast cancer (BC) patients. It is, however, unclear whether changes in serum levels can be exploited for early detection or classification of patients into different risk/disease categories. In our study, we measured concentration and activity of MMP2/9 in sera of 345 donors classified as low risk (Gail score <1.7), high risk (HR) (Gail score ≥1.7), benign disease or BC. Kruskal–Wallis and Mann–Whitney nonparametric tests showed that total‐MMP2 concentration is higher in HR compared to control (p = 0.012), benign (p = 0.001) and cancer (p = 0.007). Active MMP2 (aMMP2) concentration is higher in control than benign and cancer (p < 0.001, respectively). Total and aMMP9 concentrations are higher in cancer than benign (p < 0.001, p = 0.002, respectively). Total‐MMP2 and total‐MMP9 activities are lower in control than benign (p < 0.001, p = 0.002, respectively) and cancer (p < 0.001, respectively). Total‐MMP2 and MMP9 activities are also higher in cancer than benign (p = 0.004, p < 0.001) and HR (p = 0.008, p = 0.007, respectively). These results were not affected by age or inclusion/exclusion of donors with noninvasive cancer or atypical hyperplasia. Linear discriminant analysis revealed that HR donors are characterized by lower total‐MMP2 and higher aMMP2. Overall group classification accuracy was 64.5%. Independent validation based on the leave‐one‐out cross validation approach gave an overall classification of 63%. Our study provides evidence supporting the potential role of serum MMP2/9 as biomarkers for breast disease classification.

Expression of the Sodium Iodide Symporter and Thyroglobulin Genes Are Reduced in Papillary Thyroid Cancer

Altered expression of the gene encoding the sodium iodine symporter (NIS) may be an important factor that leads to the reduced iodine accumulation characteristic of most benign and malignant thyroid nodules. Both up- and down-regulation of NIS gene expression have been reported in thyroid cancer using several different methods. The goal of the present study was to accurately identify alterations in NIS gene expression in benign and malignant thyroid nodules using an accurate real-time quantitative RT-PCR assay system. Total RNA was prepared from 18 benign thyroid nodules, 20 papillary thyroid cancers, and 23 normal thyroid samples from 38 subjects. Quantitative RT-PCR was used to measure NIS and thyroglobulin (TG) mRNA expression in normal thyroid tissue and in each nodular tissue sample. Papillary thyroid cancer samples had significantly lower NIS mRNA expression (72 ± 41 picogram equivalents [pg Eq]), than did benign nodules (829 ± 385 pg Eq), or normal tissues (1907 ± 868 pg Eq, P = 0.04). Most important, in the paired samples, NIS gene expression was decreased in each papillary thyroid cancer compared with normal tissue (69% median decrease; range, 40–96%; P = .013). Eleven of the 12 benign nodules also demonstrated lower NIS gene expression than the normal tissue (49% decrease; range, 2–96%; P = .04). Analysis of the paired samples demonstrated that Tg mRNA expression was significantly lower in each of the thyroid cancer samples than in corresponding normal tissue (759 ± 245 pg Eq vs. 1854 ± 542 pg Eq, P = .03). We have demonstrated a significant decrement in NIS gene expression in all papillary thyroid cancers and in over 90% of benign nodules examined compared with adjacent normal thyroid tissue, using a highly accurate quantitative RT-PCR technique. Similarly, thyroid cancers demonstrated significantly lower TG mRNA expression than corresponding normal thyroid. Reduced NIS expression may be an important factor in the impairment of iodine-concentrating ability of neoplastic thyroid tissues.

Prospective randomized study comparing sentinel lymph node evaluation with standard pathologic evaluation for the staging of colon carcinoma: results from the United States Military Cancer Institute Clinical Trials Group Study GI-01.

Background:The principal role of sentinel lymph node (SLN) sampling and ultrastaging in colon cancer is enhanced staging accuracy. The utility of this technique for patients with colon cancer remains controversial. Purpose:This multicenter randomized trial was conducted to determine if focused assessment of the SLN with step sectioning and immunohistochemistry (IHC) enhances the ability to stage the regional nodal basin over conventional histopathology in patients with resectable colon cancer. Patients and Methods:Between August 2002 and April 2006 we randomly assigned 161 patients with stage I–III colon cancer to standard histopathologic evaluation or SLN mapping (ex vivo, subserosal, peritumoral, 1% isosulfan blue dye) and ultrastaging with pan-cytokeratin IHC in conjunction with standard histopathology. SLN-positive disease was defined as individual tumor cells or cell aggregates identified by hematoxylin and eosin (H&E) and/or IHC. Primary end point was the rate of nodal upstaging. Results:Significant nodal upstaging was identified with SLN ultrastaging (Control vs. SLN: 38.7% vs. 57.3%, P = 0.019). When SLNs with cell aggregates ≤0.2 mm in size were excluded, no statistically significant difference in node-positive rate was apparent between the control and SLN arms (38.7% vs. 39.0%, P = 0.97). However, a 10.7% (6/56) nodal upstaging was identified by evaluation of H&E stained step sections of SLNs among study arm patients who would have otherwise been staged node-negative (N0) by conventional pathologic assessment alone. Conclusion:SLN mapping, step sectioning, and immunohistochemistry (IHC) identifies small volume nodal disease and improves staging in patients with resectable colon cancer. A prospective trial is ongoing to determine the clinical significance of colon cancer micrometastasis in sentinel lymph nodes.

Guidelines for the Safe Use of Radioactive Materials During Localization and Resection of the Sentinel Lymph Node

Background: Several reports have demonstrated accurate prediction of nodal metastasis with radiolocalization and selective resection of the radiolocalized sentinel lymph node (SLN) in patients with breast cancer and melanoma. As reliance on this technique grows, its use by those without experience in radiation safety will increase.Methods: Tissue obtained during radioguided SLN biopsies was examined for residual radioactivity. Specimens with a specific activity greater than the radiologic control level (RCL) of 0.002μCi/g were considered radioactive. Radiation exposure to the surgical team was measured.Results: A total of 24 primary tissue specimens and 318 lymph nodes were obtained during 57 operations (37 for breast cancer, 20 for melanoma). All 24 (100%) of the specimens injected with radiopharmaceutical and 89 of 98 (91%) of the localized nodes were radioactive after surgery. Activity fell below the RCL 71 ± 3.6 hours in primary tissue specimens, 46 ± 1.7 hours in nodes from melanoma patients, and 33 ± 3.5 hours in nodes from breast cancer patients (P = .037). The hands of the surgical team (n = 22 cases) were exposed to 9.4 ± 3.6 mrem/case.Conclusion: Although low levels of radiation exposure are associated with radiolocalization and resection of the SLN, the presented guidelines ensure conformity to existing regulations and allow timely pathologic analysis.

Ultrasonographically guided injection improves localization of the radiolabeled sentinel lymph node in breast cancer

AbstractBackground: Several reports have demonstrated the accurate prediction of axillary nodal status (ANS) with radiolocalization and selective resection of sentinel lymph nodes (SLN) in breast cancer. To date, no technique has proven to be superior in localizing the SLN. Methods: 1.0 mCi of clear unfiltered99mtechnetium sulfur colloid was injected under ultraso-nographic (US) guidance around the perimeter of the breast lesion (palpable and nonpalpable) or previous biopsy site. Resection of the radiolocalized nodes was performed, followed by complete axillary lymph node dissection (AXLND). Results: Forty-two breast cancer patients underwent SLN biopsy after US-guided radiopharmaceutical injection. The SLN was localized in 41 patients (98%). The type of previously performed diagnostic biopsy did not influence the ability to localize the sentinel lymph node. Pathology revealed nodal metastasis in 7 of the 41 evaluable patients (17%). ANS was accurately predicted in 40 of 41 patients (98%). Conclusions: Early experience with radiologicalization and selective resection of SLN in breast cancer remains promising. Use of US-guided injection facilitates localization of the SLN, perhaps as a result of more accurate placement of the radionuclide marker. Use of this technique allowed for effective management of patients regardless of tumor size or the extent of prior biopsy, thereby expanding the potential number of eligible patients for SLN biopsy.

A prospective evaluation of patients undergoing surgery for the palliation of an advanced malignancy.

BackgroundDecisions regarding the use of surgical procedures for the palliation of symptoms caused by advanced malignancies require the highest level of surgical judgment. Prospective analysis of palliative surgical care may facilitate a more effective and representative evaluation of these patients.MethodsPatients requiring surgery planned solely for the palliation of an advanced malignancy were offered entry onto this study. Outcome measurements were made before surgery and monthly thereafter until the patient’s death. Accepted techniques of pain assessment, quality of life, and functional status were used.ResultsBetween May 1997 and December 1999, 26 patients were enrolled. Although 46% (12 of 26) of patients demonstrated improvement in pain control or quality of life after palliative surgery, these benefits lasted a median of only 3.4 months. Palliative surgery was associated with significant postoperative complications in 35% (9 of 26) patients.ConclusionsAlthough many patients had no apparent demonstrable benefit from surgery, surgeons were able to identify a group of patients who experienced significant benefits after a palliative procedure. The relationships between the patient and family members and the surgeon play an important role in decision-making throughout the palliative phase of cancer treatment.

Electrical Impedance Scanning for the Early Detection of Breast Cancer in Young Women: Preliminary Results of a Multicenter Prospective Clinical Trial

PURPOSE To evaluate the feasibility and patient satisfaction with electrical impedance scanning (EIS) for early detection of breast cancer in young women. METHODS Women undergoing screening clinical breast examination, imaging, or biopsy were eligible for EIS examination with T-Scan 2000ED (Mirabel Medical Systems, Austin, TX). Multiple logistic regression analysis evaluated the association between clinical variables and EIS performance. Patients completed a screening EIS satisfaction questionnaire (1 = least satisfied to 5 = most satisfied). RESULTS Twenty-nine cancers were identified among 1,103 women. Sixty-six percent (19 of 29) of cancers were nonpalpable and 55% (16 of 29) were in women age < or = 50 years. EIS sensitivity and specificity in women younger than 40 years was 50% and 90%, respectively. Exogenous estrogen use (P < .001) and menopausal status (P = .007) correlated significantly with EIS performance. False-positive rates were increased in postmenopausal women and those taking exogenous hormones. No correlation was evident between EIS performance and family history, prior breast cancer, breast density, or palpability. EIS-positive women younger than age 40 were 4.5 times more likely to have breast carcinoma than were women randomly selected from the general population. Patients were highly satisfied with the comfort, speed, and reporting of EIS screening (mean score, 4.8). CONCLUSION EIS seems promising for early detection of breast cancer, and identification of young women at increased risk for having the disease at time of screening. Positive EIS-associated breast cancer risk compares favorably with relative risks of conditions commonly used to justify early breast cancer screening. Patients are satisfied with a screening paradigm involving breast EIS.

Loss of Nuclear Localized and Tyrosine Phosphorylated Stat5 in Breast Cancer Predicts Poor Clinical Outcome and Increased Risk of Antiestrogen Therapy Failure

PURPOSE To investigate nuclear localized and tyrosine phosphorylated Stat5 (Nuc-pYStat5) as a marker of prognosis in node-negative breast cancer and as a predictor of response to antiestrogen therapy. PATIENTS AND METHODS Levels of Nuc-pYStat5 were analyzed in five archival cohorts of breast cancer by traditional diaminobenzidine-chromogen immunostaining and pathologist scoring of whole tissue sections or by immunofluorescence and automated quantitative analysis (AQUA) of tissue microarrays. RESULTS Nuc-pYStat5 was an independent prognostic marker as measured by cancer-specific survival (CSS) in patients with node-negative breast cancer who did not receive systemic adjuvant therapy, when adjusted for common pathology parameters in multivariate analyses both by standard chromogen detection with pathologist scoring of whole tissue sections (cohort I; n = 233) and quantitative immunofluorescence of a tissue microarray (cohort II; n = 291). Two distinct monoclonal antibodies gave concordant results. A progression array (cohort III; n = 180) revealed frequent loss of Nuc-pYStat5 in invasive carcinoma compared to normal breast epithelia or ductal carcinoma in situ, and general loss of Nuc-pYStat5 in lymph node metastases. In cohort IV (n = 221), loss of Nuc-pYStat5 was associated with increased risk of antiestrogen therapy failure as measured by univariate CSS and time to recurrence (TTR). More sensitive AQUA quantification of Nuc-pYStat5 in antiestrogen-treated patients (cohort V; n = 97) identified by multivariate analysis patients with low Nuc-pYStat5 at elevated risk for therapy failure (CSS hazard ratio [HR], 21.55; 95% CI, 5.61 to 82.77; P < .001; TTR HR, 7.30; 95% CI, 2.34 to 22.78; P = .001). CONCLUSION Nuc-pYStat5 is an independent prognostic marker in node-negative breast cancer. If confirmed in prospective studies, Nuc-pYStat5 may become a useful predictive marker of response to adjuvant hormone therapy.