The prognostic value of the stem-like group in colorectal cancer using a panel of immunohistochemistry markers.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the Western world. It is becoming increasingly clear that CRC is a diverse disease, as exemplified by the identification of subgroups of CRC tumours that are driven by distinct biology. Recently, a number of studies have begun to define panels of diagnostically relevant markers to align patients into individual subgroups in an attempt to give information on prognosis and treatment response. We examined the immunohistochemical expression profile of 18 markers, each representing a putative role in cancer development, in 493 primary colorectal carcinomas using tissue microarrays. Through unsupervised clustering in stage II cancers, we identified two cluster groups that are broadly defined by inflammatory or immune-related factors (CD3, CD8, COX-2 and FOXP3) and stem-like factors (CD44, LGR5, SOX2, OCT4). The expression of the stem-like group markers was associated with a significantly worse prognosis compared to cases with lower expression. In addition, patients classified in the stem-like subgroup displayed a trend towards a benefit from adjuvant treatment. The biologically relevant and poor prognostic stem-like group could also be identified in early stage I cancers, suggesting a potential opportunity for the identification of aggressive tumors at a very early stage of the disease.

Lymphocytic follicles and aggregates are a determinant of mucosal damage and duration of diarrhea.

CONTEXT: Nonspecific changes (nonspecific chronic inflammation) in patients with chronic diarrhea represent the commonest diagnosis in colorectal biopsy interpretation, but these changes are of little clinical significance. OBJECTIVE: To find, within this group, histologic and immunohistologic diagnostic criteria to predict the duration and resolution of diarrhea. DESIGN: Detailed clinical features and histologic findings were analyzed in a cohort of 47 patients with chronic diarrhea, with near-normal histology and no clear-cut known etiologic agent. Immunohistochemistry to mast cells (CD117) and Treg cells (FOXP3) was also assessed in 39 patients. RESULTS: Increased number of lymphoid follicles and aggregates, increased number of mast cells, and paucity of Treg were the statistically significant key findings (P  =  .003, P  =  .008, and P  =  .04, respectively). The duration of diarrhea was correlated with the number of large lymphoid follicles and aggregates (P  =  .001, r  =  .48), number of total lymphoid follicles and aggregates (P  =  .003, r  =  .43), density of lymphoid follicles and aggregates (P  =  .009, r  =  .38), and total lymphoid follicles and aggregates per biopsy (P  =  .004, r  =  .42) and the number of mast cells (P  =  .001, r  =  .52). The number of mast cells and Treg cells showed significant difference between resolved and unresolved cases (P  =  .001 and P  =  .01 respectively). CONCLUSIONS: Lymphocytic follicles and aggregates colitis, previously regarded as of negligible diagnostic significance, allows the prediction of the behavior of chronic diarrhea in a subset of patients with nonspecific changes on colonic biopsy. The increased number of mast cells and paucity of Treg cells further helps to identify such unresolved cases.

Distribution of gemcitabine pathway genotypes in ethnic Asians and their association with outcome in non-small cell lung cancer patients.

OBJECTIVE: Pharmacogenetics suggests variants of genes involved in gemcitabine pharmacology could be useful markers for predicting inter-ethnic and inter-patient outcomes from treatment with the agent. Here, we have characterized the distribution of variants of genes involved in gemcitabine pharmacology in ethnic Asian populations and their association with non-small cell lung cancer (NSCLC) patient outcome. METHODS: All genes involved in gemcitabine transport, metabolism and activity were screened for suitable variants for analysis using publications and public databases. By pyrosequencing, the frequency of qualifying variants was characterized from germline DNA of 94 healthy Asian donors and 53 NSCLC patients receiving gemcitabine-based chemotherapy. RESULTS: Significant differences in genotype distribution between Caucasians and Asians were seen at 10/25 (45%) variant loci. In NSCLC patients, CDA+435 C>T variants were associated with response (p=0.026) and time to progression (p=0.016) and SLC28A1+1561 G>A variants were associated with neutropenia (p=0.030) and thrombocytopenia nadir (p=0.037). CONCLUSIONS: Many genotypes in gemcitabine pharmacology vary in their frequency between Caucasians and Asians. CDA+435, and SLC28A1+1561 are worthy of further investigation as potential indicators of patient outcome after gemcitabine treatment.

Clonal characterization of sporadic cribriform-morular variant of papillary thyroid carcinoma by laser microdissection-based APC mutation analysis.

Cribriform-morular variant (C-MV) of papillary thyroid carcinoma (PTC) is a rare and unusual neoplasm composed of multiple histologic components, including cribriform, papillary, solid, tall columnar, and morular patterns. Analyses of gross C-MV of PTC lesions has linked adenomatous polyposis coli (APC) mutations to its pathogenesis; however, the extent of involvement of mutations in the development of individual components is unclear. We report on bidirectional sequencing of the mutation cluster region (codons 1032-1565) of the APC gene in individually laser-microdissected components of a previously unreported C-MV of PTC. A silent Thr1493Thr gene variant was found in all tumoral components, whereas a 5-base-pair frameshift deletion at codon 1309 was identified only in the morules. Neither variant was observed in matched normal thyroid tissue. These results show the histologic components of C-MV of PTC to have some common mutational background, although additional somatic mutations may be involved in the development of morular structures.

Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population.

BACKGROUND: Chinese and Malay subjects have been reported to require less maintenance warfarin than Indians that could not be accounted for by cytochrome P450 (CYP) 2C9 variants. Vitamin K epoxide reductase complex 1 (VKORC1) is the target enzyme of warfarin, and VKORC1 intronic variants and haplotypes have recently been shown to influence VKORC1 activity and warfarin requirements. METHODS: We sequenced the coding regions of CYP2C9 and VKORC1 and inferred VKORC1 haplotype from 10 intronic variants in 147 Chinese, 85 Malay, and 43 Indian patients receiving maintenance warfarin. RESULTS: The mean weight-normalized warfarin dose was lower for Chinese and Malays than for Indians (0.058 +/- 0.025 mg/kg, 0.059 +/- 0.023 mg/kg, and 0.089 +/- 0.036 mg/kg, respectively; P < .001 for comparisons between Chinese and Malays with Indians). CYP2C9*2 and VKORC1 coding region variants were rare (<2%), whereas CYP2C9*3 associated with lower warfarin requirements was less common in Chinese and Malays (7% and 9%, respectively) than in Indians (18%) and could not account for their lower warfarin requirements. VKORC1 H1 and H7/H8/H9 haplotypes were associated with lower and higher warfarin requirements, respectively (0.050 +/- 0.019 mg/kg and 0.092 +/- 0.057 mg/kg, respectively; P < .001). VKORC1 H1 haplotype (requiring low warfarin doses) was common in Chinese (87%) and Malays (65%) but uncommon in Indians (12%), whereas H7, H8, and H9 haplotypes (requiring high warfarin doses) were rare in Chinese (9%), intermediate in Malays (30%), and common in Indians (82%). The interethnic difference in warfarin requirements became nonsignificant when adjusted for VKORC1 haplotype. CONCLUSIONS: Interethnic difference in VKORC1 haplotypes accounts for the difference in warfarin requirements between Chinese, Malays, and Indians, providing interesting insights into genetic variation between ethnogeographically distinct Asian groups.