The Genotype-Tissue Expression (GTEx) project, sponsored by the NIH Common Fund, was established to study the correlation between human genetic variation and tissue-specific gene expression in ...non-diseased individuals. A significant challenge was the collection of high-quality biospecimens for extensive genomic analyses. Here we describe how a successful infrastructure for biospecimen procurement was developed and implemented by multiple research partners to support the prospective collection, annotation, and distribution of blood, tissues, and cell lines for the GTEx project. Other research projects can follow this model and form beneficial partnerships with rapid autopsy and organ procurement organizations to collect high quality biospecimens and associated clinical data for genomic studies. Biospecimens, clinical and genomic data, and Standard Operating Procedures guiding biospecimen collection for the GTEx project are available to the research community.
We conducted a randomized trial comparing adjuvant treatment with edrecolomab versus observation in patients with resected, low-risk, stage II colon cancer. This study also prospectively studied ...patient- and tumor-specific markers of treatment outcome.
After surgical resection, patients with stage II colon cancer were randomly assigned to either five infusions of edrecolomab at 28-day intervals or observation without adjuvant therapy.
Final accrual included 1,738 patients; 865 patients received edrecolomab, and 873 patients were observed without adjuvant treatment. Median follow-up time was 7.9 years. There were no significant outcome differences between study arms (overall survival OS, P = .71; disease-free survival, P = .64). The combined 5-year all-cause OS was 0.86 (95% CI, 0.84 to 0.88), and the combined 5-year disease-specific OS was 0.93 (95% CI, 0.91 to 0.94). The relationships between demographic and histopathologic factors and survival differed for all-cause and disease-specific survival outcomes, but no combined prognostic factor model was found to adequately classify patients at higher risk of recurrence or death as a result of colon cancer.
Edrecolomab did not prolong survival. Consequently, this large study with a long duration of follow-up provided unique data concerning the natural history of resected stage II colon cancer. Prognostic factors identified in previous retrospective and pooled analyses were associated with survival outcomes in this stage II patient cohort. Results from ongoing molecular marker studies may enhance our ability to determine the risk profile of these patients.
The TP53 tumor suppressor is frequently mutated in colon cancer, but the influence of such mutations on survival remains controversial. We investigated whether mutations in the DNA-binding domain of ...TP53 are associated with survival in stage III colon cancer.
The impact of TP53 genotype was prospectively evaluated in Cancer and Leukemia Group B 89803, a trial that randomized stage III colon cancer patients to receive adjuvant 5-fluorouracil/leucovorin (5FU/LV) or 5FU/LV with irinotecan (IFL).
TP53 mutations were identified in 274 of 607 cases. The presence of any TP53 mutation did not predict disease-free survival (DFS) or overall survival with either adjuvant regimen when men and women were considered together or as separate groups. However, outcome differences among women became apparent when tumor TP53 genotype was stratified as wild-type versus zinc- or non-zinc-binding mutations in the TP53 DNA-binding domain. DFS at 5 years was 0.59, 0.52, and 0.78 for women with TP53 wild-type tumors, and tumors with zinc- or non-zinc-binding mutations, respectively. Survival at 5 years for these same women was 0.72, 0.59, and 0.90, respectively. No differences in survival by TP53 genotype were observed in men.
The presence of any TP53 mutation within the DNA-binding domain did not predict survival in stage III colon cancer. However, TP53 genotype was predictive of survival in women following adjuvant therapy. Future colon cancer therapeutic trials, with inclusion of correlative molecular markers, should be designed to permit evaluation of survival and/or response to treatment in women separately from men.
The pathogenesis of colorectal carcinoma is characterized by progressive genetic abnormalities, which lead to proteomic and cellular changes that determine the cancer malignant phenotype. Phenotypic ...characteristics seen on histopathologic examination (e.g., tumor stage, histologic grade, and vasoinvasiveness) are essential to planning patient management and should continue to be the major focus of pathologists' efforts. Nonetheless, additional markers that improve the prognostic and predictive power of the pathologic analysis of the primary tumor have been the focus of intense research in recent years. Improved prognostic power may derive from advancements in histopathologic evaluation, more sensitive lymph node staging techniques, and specific molecular analysis methods, such as genetic tests or immunophenotypic profiles. Histopathologic improvements are needed to better standardize histologic grade determination and recognize tumor budding at the invasive front as a marker of aggressive biological behavior and an adverse parameter. Ultrastaging of mesenteric lymph nodes remains a controversial area. Genotypic studies are well developed in the areas of microsatellite instability and chromosome 18q deletion/loss of heterozygosity. Immunophenotypic studies are available in a range of areas including tumor suppressor gene/oncogene expression, proliferation/apoptosis, angiogenesis, and cell adhesion and signaling. Gene expression profiles identified by microarray techniques may help to subtype the large category of microsatellite-stable colorectal carcinoma and define immunophenotypic panels to subclassify tumors into prognostic and therapeutic groups. This brief review discusses the most promising of these approaches and evidence supporting their potential clinical utility.
The Pathology Committee of the Cancer and Leukemia Group B (CALGB) is broadly and deeply integrated into the multidisciplinary clinical and scientific operations of the group. It has five major ...functions in CALGB. First, it insures the highest possible quality of pathologic data in tissue-based correlative science studies through comprehensive quality control of all tissues collected, banked, and distributed to investigators and of all morphology-based studies done within the CALGB. Within this context, the Pathology Committee has the goal of eliminating, to the greatest degree possible, variation in methodology, interpretation, and reporting of pathologic data that would compromise reproducibility of correlative science results and to assure accuracy, uniformity, and completeness of the pathologic data. Second, the committee provides expert pathologic consultation in the development of clinical trials and correlative science studies that involve pathologic issues and/or materials. Third, it provides high-quality tissue banking and centralized morphology-based technical support services (e.g., histologic sections for immunohistochemistry, tissue microarrays, etc.) for all CALGB investigators. Fourth, it initiates and executes high-quality pathologic research using CALGB and intergroup resources. Lastly, it provides group-wide education on pathology-related issues relevant to trial design, scientific study design, and specimen banking.
Carcinoma of the anal canal Ryan, D P; Compton, C C; Mayer, R J
The New England journal of medicine,
03/2000, Letnik:
342, Številka:
11
Journal Article
Recenzirano
Despite the rarity of carcinoma of the anal canal, remarkable progress has been achieved during the past 30 years in understanding its pathogenesis and improving treatment. Largely because of the ...rigorous collection of data and the treatment of patients in clinical trials, it is now widely accepted that the majority of cases are caused by human papillomavirus and can be cured by combination therapy. Concomitant treatment with external-beam radiation therapy and chemotherapy with fluorouracil and mitomycin represents the standard approach to combination treatment. Appropriate cytologic screening of high risk populations and the integration of platinum compounds into treatment regimens will most likely reduce mortality from this disorder even further.
Background & Aims: Optical coherence tomography (OCT) is an imaging technique that produces high-resolution cross-sectional images in vivo. The aim of this study was to establish the sensitivity and ...specificity of OCT for diagnosing specialized intestinal metaplasia (SIM). Methods: OCT was used to image the stomach and esophagus of 121 patients. A total of 288 biopsycorrelated OCT images were acquired. OCT criteria for SIM were formulated by analyzing 75 images of SIM. The SIM image criteria were retrospectively tested by applying them to images of gastric, squamous, SIM, and cardiac epithelium. The criteria were then tested prospectively to determine the sensitivity and specificity of OCT for diagnosing SIM. Results: OCT images of SIM are characterized by (1) absence of the layered structure of normal squamous epithelium and the vertical “pit and crypt” morphology of gastric mucosa, (2) disorganized architecture with inhomogeneous tissue contrast and an irregular mucosal surface, and (3) presence of submucosal glands. These criteria were 100% sensitive and 93% specific for SIM when applied retrospectively and 97% sensitive and 92% specific when tested prospectively. Conclusions: OCT is highly sensitive and specific for SIM and may aid in the diagnosis and surveillance of this preneoplastic lesion.
Loss of PTEN tumor suppressor function is observed in tumors of breast, prostate, thyroid, and endometrial origin. Allelic losses in the proximity of the PTEN locus (10q23) also occur in sporadic ...colorectal cancers (CRCs), but biallelic inactivation of this site has not been frequently demonstrated. We hypothesized that alternative mechanisms of PTEN allelic inactivation, such as promoter hypermethylation, might be operative in CRC and that PTEN inactivation may be related to recognized forms of genomic instability. We characterized a cohort of 273 sporadic CRCs by determining their microsatellite instability (MSI) status. Of these, 146 cancers were examined for PTEN promoter methylation by methylation-specific PCR. Mutations at the poly(A)6 repeat sequences in PTEN exons 7 and 8 and deletions at the 10q23 locus were also identified using microsatellite analysis. The presence of PTEN protein was determined by immunostaining, and the results were correlated with the promoter methylation status. We observed that PTEN promoter hypermethylation was a frequent occurrence in MSI-high (MSI-H) tumors (19.1% of MSI-H versus 2.2% of MSI-low/microsatellite stable tumors; P = 0.002). A PTEN mutation or a deletion event was present in 60% of the tumors with promoter region hypermethylation. Hypermethylation of the PTEN promoter correlated significantly with either decreased or complete loss of PTEN protein expression (P = 0.004). This is the first demonstration of PTEN inactivation as a result of promoter hypermethylation in MSI-H sporadic CRCs. These data suggest that this silencing mechanism plays a major role in PTEN inactivation and, in colon cancer, may be more important than either allelic losses or inactivating mutations. The significant correlation of PTEN hypermethylation with MSI-H tumors further suggests that PTEN is an additional important "target" of methylation along with the hMLH1 gene in the evolution of MSI-H CRCs and also confers the "second hit" in the biallelic inactivation mechanism for some proportion of tumors.
We postulated that the pathologic evaluation of the lymph nodes of surgical specimens from patients with rectal cancer can have a substantial impact on time to relapse and survival.
We analyzed data ...from 1,664 patients with T3, T4, or node-positive rectal cancer treated in a national intergroup trial of adjuvant therapy with chemotherapy and radiation therapy. Associations between the number of lymph nodes found by the pathologist in the surgical specimen and the time to relapse and survival outcomes were investigated.
Patients were divided into groups by nodal status and the corresponding quartiles of numbers of nodes examined. The number of nodes examined was significantly associated with time to relapse and survival among patients who were node-negative. For the first through fourth quartiles, the 5-year relapse rates were 0.37, 0.34, 0.26, and 0.19 (P: = .003), and the 5-year survival rates were 0.68, 0.73, 0.72, and 0.82 (P: = .02). No significant differences were found by quartiles among patients determined to be node-positive. We propose that observed differences are primarily related to the incorrect determination of nodal status in node-negative patients. Approximately 14 nodes need to be studied to define nodal status accurately.
These results suggest that the pathologic assessment of lymph nodes in surgical specimens is often inaccurate and that examining greater number of nodes increases the likelihood of proper staging. Some patients who might benefit from adjuvant therapy are misclassified as node-negative due to incomplete sampling of lymph nodes.
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