Olagunju A. Ogunbiyi

Crohn’s disease and the NOD2 gene: a role for paneth cells

BACKGROUND & AIMS The NOD2 gene, which is strongly associated with susceptibility to Crohns disease (CD) of the terminal ileum, interacts with bacterial lipopolysaccharide (LPS), inducing cellular activation. However, the mechanisms by which NOD2 mutations cause terminal ileitis are unknown, and NOD2 is expressed most highly by peripheral blood monocytes, which are distributed ubiquitously and readily respond to LPS via cell-surface receptors. Paneth cells on the other hand, are most numerous in the terminal ileum, are critically important in enteric antibacterial defense, and respond to LPS through as yet undefined pathways. We therefore determined if these specialized intestinal epithelial cells also expressed the NOD2 gene. METHODS In situ hybridization, immunohistochemistry, and laser-capture microdissection were used to determine RNA and protein expression in tissue sections, and real-time reverse-transcription polymerase chain reaction (RT-PCR) was used to quantitate gene expression in intestinal epithelial cells and peripheral blood mononuclear cells. RESULTS NOD2 was detected readily in monocytes, but not in mature macrophages in the lamina propria or within granulomas, and levels declined as monocytes differentiated into macrophages in vitro, so that Caco-2 cells expressed more NOD2 mRNA than macrophages. NOD2 mRNA was enriched in crypts compared with villi, and in situ, Paneth cells were the most prominent cells expressing NOD2 in normal and CD-affected intestinal tissue, where they also strongly expressed tumor necrosis factor alpha (TNFalpha) RNA. CONCLUSIONS The NOD2 gene product is most abundant in Paneth cells in the terminal ileum, which could therefore play a critical and hitherto unrecognized role in the pathogenesis of NOD2-associated CD.

Detection of recurrent and metastatic colorectal cancer: Comparison of positron emission tomography and computed tomography

AbstractBackground: This study evaluates the clinical value of positron emission tomography (PET) with 2-[F-18] fluoro-2-deoxy-D-glucose (FDG) as compared to computed tomography (CT) in patients with suspected recurrent or metastatic colorectal cancer (CRC). Methods: A retrospective review of the records of 58 patients who had FDG-PET for evaluation of recurrent or advanced primary CRC was performed. FDG-PET results were compared with those of CT and correlated with operative and histopathologic findings, or with clinical course and autopsy reports. Results: Recurrent or advanced primary CRC was diagnosed in 40 and 11 patients, respectively. The sensitivity and specificity of FDG-PET were 91% and 100% for detecting local pelvic recurrence, and 95% and 100% for hepatic metastases. These values were superior to CT, which had sensitivity and specificity of 52% and 80% for detecting pelvic recurrence, and 74% and 85% for hepatic metastases. FDG-PET correctly identified pelvic recurrence in 19 of 21 patients; CT was negative in 6 of these patients and equivocal in 4. FDG-PET was superior to CT in detecting multiple hepatic lesions and influenced clinical management in 10 of 23 (43%) patients. Conclusion: FDG-PET is more sensitive than CT in the clinical assessment of patients with recurrent or metastatic CRC, and provides an accurate means of selecting appropriate treatment for these patients.

Usefulness of FDG-PET scan in the assessment of suspected metastatic or recurrent adenocarcinoma of the colon and rectum

PURPOSE: The purpose of this study was to evaluate the clinical efficacy of positron emission tomography with 2-[18F] fluoro-2-deoxy-D-glucose compared with computed tomography plus other conventional diagnostic studies in patients suspected of having metastatic or recurrent colorectal adenocarcinoma. METHODS: The records of 105 patients who underwent 101 computed tomography and 109 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography scans for suspected metastatic or recurrent colorectal adenocarcinoma were reviewed. Clinical correlation was confirmed at time of operation, histopathologically, or by clinical course. RESULTS: The overall sensitivity and specificity of 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography in detection of clinically relevant tumor were higher (87 and 68 percent) than for computed tomography plus other conventional diagnostic studies (66 and 59 percent). The sensitivity of 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography in detecting mucinous cancer was lower (58 percent; n=16) than for nonmucinous cancer (92 percent; n=93). The sensitivity of 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography in detecting locoregional recurrence (n=70) was higher than for computed tomography plus colonoscopy (90vs. 71 percent, respectively). The sensitivity of 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography in detecting hepatic metastasis (n=101) was higher than for computed tomography (89vs. 71 percent). The sensitivity of 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography in detecting extrahepatic metastases exclusive of locoregional recurrence (n=101) was higher than for computed tomography plus other conventional diagnostic studies (94vs. 67 percent). 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography altered clinical management in a beneficial manner in 26 percent of cases (26/101) when compared with evaluation by computed tomography plus other conventional diagnostic studies. CONCLUSION: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography is more sensitive than computed tomography for the detection of metastatic or recurrent colorectal cancer and may improve clinical management in one-quarter of cases. However, 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography is not as sensitive in detecting mucinous adenocarcinoma, possibly because of the relative hypocellularity of these tumors.

Utility of FDG-PET for investigating unexplained plasma CEA elevation in patients with colorectal cancer.

OBJECTIVE To assess the potential role of positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (FDG) in patients with unexplained rising carcinoembryonic antigen (CEA) levels after the treatment of colorectal cancer. BACKGROUND A rising CEA level after the resection of colorectal cancer is an early indicator of tumor recurrence. However, conventional imaging techniques have limited sensitivity for detecting recurrent disease in such patients. Especially after surgical intervention, FDG-PET is rapidly gaining an important role in establishing the extent of disease in the oncology patient. METHODS Twenty-two patients with abnormal CEA levels and normal results of conventional methods of tumor detection were studied with FDG-PET. The PET results were compared with pathologic findings (n = 9) and long-term radiologic and clinical follow-up (n = 13). RESULTS FDG-PET was abnormal in 17 of 22 patients. Tissue sampling was available in 7 of these 17 patients; all of these had recurrent disease. Definitive curative surgical intervention was performed in four patients. Subsequent dedicated imaging findings and clinical course confirmed the presence of extensive disease in 8 of the remaining 10 patients; the PET results in the other 2 patients were considered falsely positive. FDG-PET was negative in 5 of 22 patients. No disease was found by tissue sampling (n = 2) and clinical follow-up (n = 3). Overall, the positive-predictive value for PET was 89%, (15 of 17) and the negative-predictive value was 100% (5 of 5). CONCLUSIONS When conventional examinations are normal, FDG-PET is a valuable imaging tool in patients who have a rising CEA level after colorectal surgery.

Confirmation that chromosome 18q allelic loss in colon cancer is a prognostic indicator.

PURPOSE Recent studies suggest that allelic loss of sequences from the long arm of chromosome 18 may be a useful prognostic indicator in colorectal cancer. The aim of the present study was to confirm whether 18q loss of heterozygosity (LOH) is of prognostic value in patients with colon cancer. METHODS Genomic DNA was prepared from archival tumor and corresponding normal tissue specimens from 151 patients who had undergone potentially curative surgery for adenocarcinoma of the colon. Polymerase chain reaction (PCR) was used to assess allelic loss of five chromosome 18q microsatellite markers in the tumors. The relationship between allelic loss and disease-free and disease-specific survival was investigated. RESULTS LOH was detected in 67 of 126 tumors. Chromosome 18q allelic loss was a negative prognostic indicator of both disease-free (relative risk [RR], 1.65; P = .01) and disease-specific survival (RR, 2.0; P = .003). 18q loss was also associated with significantly reduced disease-free and disease-specific survival in patients with stage II (P = .05 and P = .0156) and III (P = .038 and P = .032) disease. CONCLUSION Chromosome 18q allelic loss is a prognostic marker in colorectal cancers. Chromosome 18 LOH studies may be useful in identifying patients with stage II disease who are at high risk for recurrence, and as such might benefit from adjuvant chemotherapy.

Aggressive surgical management of recurrent rectal cancer - Is it worthwhile?

OBJECTIVE: The purpose of this study was to determine whether radical surgery in appropriately selected patients who have recurrent rectal cancer can produce significant disease-free survival. PATIENTS AND METHODS: This is a retrospective review of the management of all patients presenting with recurrent local and metastatic rectal cancer at a single institution during an 11-year period. RESULTS: Of 489 patients who underwent curative surgery for primary rectal cancer during the period reviewed, 44 (9 percent) developed recurrent disease at a median interval of 18 (range, 3–60) months after curative surgery. Local pelvic recurrence alone was present in 28 (5.7 percent) patients. Overall survival after diagnosis of recurrent disease was 41 percent (18/44) at a median interval of 15 (range, 2–60) months. Curative resection was performed in 14 (32 percent) patients with a disease-free survival of 86 percent (12/14) at a median of 25 (range, 9–60) months after curative surgery. In comparison, survival in patients who underwent palliative treatment was significantly less (25 vs.12 months;P<0.05; 95 percent confidence interval, 10, 23 (Mann-WhitneyUtest)); 20 percent survival at a median of 12 months ranged from 2 to 36 after diagnosis of recurrent disease. Of six patients in the curative group who developed second recurrences, four underwent further curative surgery and are disease-free at a median of 19.5 (range, 12–29) months after surgery. Palliative surgery provided good symptomatic relief and improved quality of life in 11 patients in the palliative group, although there was no survival advantage over those who underwent nonsurgical palliative treatment (n=19). CONCLUSION: In appropriately selected cases, aggressive surgical therapy produces significant disease-free survival in patients with recurrent rectal cancer.

Prognostic Value of Chromosome 1p Allelic Loss in Colon Cancer

BACKGROUND & AIMS Current evidence suggests that there may be a tumor-suppressor gene on chromosome 1p associated with colorectal cancer. The aim of the present study was to determine whether allelic loss on chromosome 1p is of prognostic value in colorectal cancer. METHODS Polymerase chain reaction was used to assess allelic loss of five chromosome 1p microsatellite markers in tumor specimens. Genomic DNA was prepared from archival tumor and corresponding normal tissue specimens from 116 patients who had undergone curative treatment for adenocarcinoma of the colon. Allelic loss was correlated with disease-free interval and survival. RESULTS Deletion of 1p sequence was detected in 22 of 82 tumors. Deletions of the microsatellite markers D1S228 (1p36) and HY-TM1 (1p32) were significantly associated with poor survival (P < 0.05): relative risk, 4.1; 95% confidence interval, 1.25-9.23 for D1S228; and relative risk, 6.6; 95% confidence interval, 1.4-19 for HY-TM1. Loss of heterozygosity at D1S228 was also associated with shorter disease-free interval: relative risk, 4.5; 95% confidence interval, 1.3-11. CONCLUSIONS Allelic loss in the 1p36 and 1p32 regions of chromosome 1 appears to be an independent predictor of poor prognosis in patients with adenocarcinoma of the colon.

Selection criteria for treatment of rectal cancer with combined external and endocavitary radiation.

PURPOSE: The aim of this study was to identify factors predictive of recurrence of rectal tumors treated with combined external and endocavitary radiation. METHODS: Seventy-two patients with rectal cancer were evaluated clinically and with transrectal ultrasound before combined external and endocavitary radiation. Ideal lesions were moderately differentiated, mobile, not ulcerated, <3 cm in diameter, and <12 cm from the anal verge. External radiation (4,500 cGy) was given during five weeks followed by endocavitary radiation (3,000 cGy × 2). Median follow-up was 31 (range, 7–93) months. RESULTS: Pretreatment transrectal ultrasound stages were uT1 (6 patients), uT2(27 patients), and uT3 (39 patients). Clinical evaluation identified 26 ideal and 46 nonideal tumors. Overall recurrence was 36 percent; mean time to recurrence was 12 months. Ideal lesions recurred less than nonideal (15vs. 48 percent;P=0.01). Mobile lesions recurred less than tethered lesions (26vs. 52 percent;P=0.048). Transrectal ultrasound stage was predictive of recurrence (0 percent uT1, 22 percent uT2, and 51 percent uT3;P=0.015). Surgery was possible in 14 of 17 patients with pelvic recurrence only; 11 patients (65 percent) had curative surgery. Distant metastases occurred in nine patients; all had pelvic recurrences, and six died of disease. CONCLUSION: Patients with uT3 or nonideal rectal cancers should not be offered combined external and endocavitary radiation for cure. Transrectal ultrasound stage is the only independent predictor of recurrence.