Routine molecular screening of patients with colorectal adenocarcinoma for the Lynch syndrome identified mutations in patients and their family members that otherwise would not have been detected. These data suggest that the effectiveness of screening with immunohistochemical analysis of the mismatch-repair proteins would be similar to that of the more complex strategy of genotyping for microsatellite instability.
A B S T R A C T PurposeIdentifying individuals with Lynch syndrome (LS) is highly beneficial. However, it is unclear whether microsatellite instability (MSI) or immunohistochemistry (IHC) should be used as the screening test and whether screening should target all patients with colorectal cancer (CRC) or those in high-risk subgroups. Patients and MethodsMSI testing and IHC for the four mismatch repair proteins was performed on 500 tumors from unselected patients with CRC. If either MSI or IHC was abnormal, complete mutation analysis for the mismatch repair genes was performed. ResultsAmong the 500 patients, 18 patients (3.6%) had LS. All 18 patients detected with LS (100%) had MSI-high tumors; 17 (94%) of 18 patients with LS were correctly predicted by IHC. Of the 18 probands, only eight patients (44%) were diagnosed at age younger than 50 years, and only 13 patients (72%) met the revised Bethesda guidelines. When these results were added to data on 1,066 previously studied patients, the entire study cohort (N ϭ 1,566) showed an overall prevalence of 44 of 1,566 patients (2.8%; 95% CI, 2.1% to 3.8%) for LS. For each proband, on average, three additional family members carried MMR mutations. ConclusionOne of every 35 patients with CRC has LS, and each has at least three relatives with LS; all of whom can benefit from increased cancer surveillance. For screening, IHC is almost equally sensitive as MSI, but IHC is more readily available and helps to direct gene testing. Limiting tumor analysis to patients who fulfill Bethesda criteria would fail to identify 28% (or one in four) cases of LS.
Objective Pain, depression, and fatigue function as a symptom cluster and thus may share common risk factors. Interpersonal relationships clearly influence health, suggesting that loneliness may promote the development of the pain, depression, and fatigue symptom cluster. We hypothesized that loneliness would be related to concurrent symptom cluster levels and increases in symptom cluster levels over time. Methods We utilized two observational studies with distinct longitudinal samples. Study 1 was a sample of cancer survivors and benign controls (N=115) assessed annually for 2 years. Study 2 was a sample of older adults caring for a spouse with dementia (caregivers) and non-caregiver controls (N=229) assessed annually for 4 years. Participants completed annual measures assessing loneliness, pain, depression, and fatigue. Results Across both samples, lonelier participants experienced more concurrent pain, depression, and fatigue and larger increases in symptom cluster levels from one year to the next than less lonely participants. Sleep quality did not mediate the results in either study. All analyses were adjusted for relevant demographic and health variables. Conclusions Two longitudinal studies with different populations demonstrated that loneliness was a risk factor for the development of the pain, depression, and fatigue symptom cluster over time. The current research helps identify people most at risk for pain, depression, and fatigue, and lays the groundwork for research about their diagnosis and treatment. These data also highlight the health risks of loneliness; pain, depression, and fatigue often accompany serious illness and place people at risk for poor health and mortality.
Background. Patients with transmurally invasive, lymph node negative colorectal carcinoma (Dukes' B) have a 5‐year survival rate ranging from 53.9% to 84.9%. The authors postulate that patients with Dukes' B colon cancer who die of their disease have occult micrometastases in their pericolic lymph nodes at the time of original diagnosis. In an attempt to identify these occult micrometastases, pericolic lymph nodes from Dukes' B colon cancer resections were stained retrospectively with antibodies against cytokeratin (anti‐keratin AE1/AE3, Boehringer Mannheim, Indianapolis, IN) and CC49 (a second‐generation monoclonal antibody directed against TAG‐72. Methods. The authors reviewed all Dukes' B (transmurally invasive, lymph node negative) primary colorectal carcinoma resection specimens from the surgical pathology files of the Ohio State University Hospitals between 1984 and 1987. Survival data were obtained from the Tumor Registry of the Arthur G. James Cancer Hospital and Research Institute, Columbus, Ohio. The results were analyzed by univariate and multivariate analysis. Results. Fifty cases with 568 lymph nodes (11.3 per case) were examined with each antibody using standard immunoperoxidase techniques. Positive staining for cytokeratin was seen in 14 patients (33 lymph nodes), 6 of whom died of colon cancer within 66 months (43%) Only 1 of the 36 patients with cytokeratin‐negative lymph nodes died of colon cancer over the same time period (3%, P = 0.0009 univariate, P = 0.0013 multivariate). There was no significant difference in survival between the CC49‐positive and CC49‐negative groups. Conclusion. Immunoperoxidase techniques are capable of identifying micrometastatic disease in lymph nodes missed by routine hematoxylin and eosin staining. Further, the presence of cytokeratin‐positive cells within lymph nodes correlated with a significantly poorer prognosis. Therefore, cytokeratin staining of pericolic lymph nodes in patients with Dukes' B colorectal cancer is recommended. Larger multicenter studies are needed, however, to confirm these results and to evaluate the appropriateness of adjuvant chemotherapy in patients whose disease is upstaged by immunohistochemical staining.
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