Pao-Shiu Hsieh

Circulating Tumor Cell Count Correlates with Colorectal Neoplasm Progression and Is a Prognostic Marker for Distant Metastasis in Non-Metastatic Patients

Enumeration of circulating tumor cells (CTCs) has been proven as a prognostic marker for metastatic colorectal cancer (m-CRC) patients. However, the currently available techniques for capturing and enumerating CTCs lack of required sensitivity to be applicable as a prognostic marker for non-metastatic patients as CTCs are even more rare. We have developed a microfluidic device utilizing antibody-conjugated non-fouling coating to eliminate nonspecific binding and to promote the multivalent binding of target cells. We then established the correlation of CTC counts and neoplasm progression through applying this platform to capture and enumerate CTCs in 2 mL of peripheral blood from healthy (n = 27), benign (n = 21), non-metastatic (n = 95), and m-CRC (n = 15) patients. The results showed that the CTC counts progressed from 0, 1, 5, to 36. Importantly, after 2-year follow-up on the non-metastatic CRC patients, we found that those who had ≥5 CTCs were 8 times more likely to develop distant metastasis within one year after curable surgery than those who had <5. In conclusion, by employing a sensitive device, CTC counts show good correlation with colorectal neoplasm, thus CTC may be as a simple, independent prognostic marker for the non-metastatic CRC patients who are at high risk of early recurrence.

Inverse Effects of Mucin on Survival of Matched Hereditary Nonpolyposis Colorectal Cancer and Sporadic Colorectal Cancer Patients

Purpose: To compare survival and histologic features of hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome) cases to well-matched sporadic colon cancers from the same patient population. Experimental Design: Between January 1995 and March 2002, a total of 5,138 consecutive patients underwent resection of primary colorectal adenocarcinoma in a single institution. According to the Amsterdam criteria, 56 HNPCC patients were matched to 147 sporadic colorectal cancer (SCRC) with no family history of cancer and with the same gender, tumor location, and age within 3 years. Immunohistochemical analyses were done for MUC1, MUC2, MUC3, and MUC5AC. Results: The HNPCC group had a marginally significantly better long-term outcome than the SCRC group (P = 0.058). The trend disappeared after adjustment by tumor-node-metastasis stage in a Cox model (P = 0.774). We noted a difference of >50% in the 5-year cancer-specific survival rates of HNPCC- and SCRC-mucinous groups (92% versus 31%, P = 0.0003). Interaction between mucin and HNPCC and its effects on survival were further confirmed by comparing the Cox models with and without interaction terms (hazard ratio, 0.1; P = 0.034 with adjusting stage). Patients with tumors showing dual expression of mucin and MUC1, which appeared in 11% of those with HNPCC and 50% of those with SCRC, had a lower 5-year cancer-specific survival rate than patients without (30% versus 60%; P = 0.004 by log-rank test; P = 0.039 with adjustment for tumor-node-metastasis stage). Conclusions: These results suggest that mucin has an inverse effect on survival in patients with HNPCC and SCRC, which might be partly explained by a lower prevalence of MUC1 expression in the mucinous HNPCC group than in the SCRC groups.

Effect of Body Mass Index on the Outcome of Patients With Rectal Cancer Receiving Curative Anterior Resection: Disparity Between the Upper and Lower Rectum

Objective:The aim of this study was to investigate the effect of body mass index (BMI) on local recurrence of primary rectal cancer after open curative sphincter-saving resection. Background:Increasing BMI was reported to be associated with a higher likelihood of local recurrence in male patients with rectal cancer. However, it remained unclear whether BMI exerts the same effects on local recurrence of rectal cancer in the upper and lower rectum. Methods:Between January 1995 and December 2002, we investigated 1873 patients with well-documented body height and body weight who underwent curative anterior resection for primary rectal cancer in a single institution. The patients were assigned to 4 groups according to their BMI: underweight, normal, overweight, and obese. Results:The frequency of local recurrence increased with an increase in the BMI in patients with lower rectal cancer. The local recurrence rates were 2.5% (2 of 79), 6.1% (48 of 782), 9.2% (39 of 424), and 13.8% (9 of 65) in underweight, normal, overweight, and obese patients with lower rectal cancer, respectively. These results were different from those of patients with upper rectal cancer. Independent risk factors for local recurrence in the lower rectal cancer group were BMI, resection margin, histologic grade of differentiation, depth of tumor invasion, and status of lymph node metastases. In the upper rectal cancer group, the depth of tumor invasion and histologic grade of differentiation reached statistical significance. Conclusions:BMI exerted different effects on local recurrence of rectal cancer in the upper and lower rectum. Further, more aggressive adjuvant and/or neoadjuvant treatments should be considered for patients with tumor in the lower rectum and with higher BMI.

Massive hematochezia from acute hemorrhagic rectal ulcer in patients with severe comorbid illness: rapid control of bleeding by per anal suturing of bleeder using anoretractor.

PurposeMassive hematochezia from acute hemorrhagic rectal ulcer can arise in patients with severe comorbid illness who are bedridden for long periods. If the bleeder is not found and treated immediately, the bleeding will cause deterioration of health and even threaten life. The results of the current study show how quickly and safely per anal suturing can treat acute hemorrhagic rectal ulcer.MethodsFrom January 2003 to December 2003, the records of 26 patients who underwent per anal suturing of acute hemorrhagic rectal ulcer were retrospectively reviewed. The identification of acute hemorrhagic rectal ulcer was confirmed by clinical and anoscopic examination.ResultsMost of these patients were elderly and bedridden (14 men; median age 69 years). Main comorbid illnesses existed in all patients and included liver cirrhosis (8 patients, 31 percent), sepsis (13 patients, 50 percent), cerebral vascular accident (15 patients, 58 percent), respiratory failure (13 patients, 50 percent), and malignancy (7 patients, 27 percent). Effective hemostasis was achieved in all patients by direct suture of bleeding ulcer. No complications developed relative to the per anal suturing procedure among any patients. Although 11 patients developed recurrent hematochezia, 9 patients responded to repeated therapy. The risk factors associated with recurrent bleeding were severity of disease and abnormal coagulation.ConclusionsWhen massive hematochezia occurs in bedridden patients with severe comorbid illness, it is essential to investigate the lower rectum, which often is affected by acute hemorrhagic rectal ulcer. Recognition of this clinical presentation will result in early identification and therapy. Per anal suturing of a bleeder at the bedside provides a quick, safe, and successful management of acute hemorrhagic rectal ulcer.

Preoperative carcinoembryonic antigen elevation in colorectal cancer.

UNLABELLED BACKGROUND /AIMS: The aim of this study was to calculate the prevalence of elevated carcinoembryonic antigen (CEA) among colorectal cancer (CRC) patients and to evaluate the prognostic value of preoperative serum CEA levels in them. METHODOLOGY Between 1995 and 2005, 8,861 consecutive patients were enrolled from a prospective database. CEA =5ng/mL was defined as elevated CEA. RESULTS In the multivariate analysis, elevated preoperative CEA correlated with higher ages, circumferential tumors, colon tumors, large tumors, liver metastasis and high-stage (AJCC) tumors. After a 44-month median follow-up, elevated CEA was found to be an independent prognostic factor (odds ratio = 1.61) for overall survival in all 4 stages of the disease. The survival among patients with stage I tumors and elevated CEA (5-year survival rate = 74.7%) was not greater than that among patients with stage II tumors and no CEA elevation (5-year survival rate = 80.8%). CONCLUSIONS Elevated preoperative CEA correlated with a higher age, circumferential tumors, colon tumors, large tumors, liver metastasis, and high-stage (AJCC) tumors. Elevated preoperative CEA indicates a potential poor prognosis even in early stage tumors. This poorer prognosis in the patients with stage I tumors and elevated preoperative CEA was not cancer specific.

Concurrent colonic mucosa-associated lymphoid tissue lymphoma and adenoma diagnosed after a positive fecal occult blood test: a case report

BackgroundColonic lymphoma is an uncommon presentation of extranodal lymphoma. Colonic mucosa-associated lymphoid tissue lymphoma is a different entity from gastric mucosa-associated lymphoid tissue lymphoma, and very rare. The presentation and management of colonic mucosa-associated lymphoid tissue are highly variable in the literature.Case presentationWe report the case of a 59-year-old Taiwanese man who underwent a colonoscopy after a positive test for fecal occult blood. His past history included hypertension and hyperthyroidism. The colonoscopy revealed an adenomatous polyp and mucosa-associated lymphoid tissue lymphoma. We successfully performed a polypectomy and endoscopic mucosal resection. The lymphoma was staged according to the Ann Arbor system modified by Musshoff as E-I. Our patient showed no lymphoma recurrence over a 3-year follow-up.ConclusionsEndoscopic mucosal resection for colonic mucosa-associated lymphoid tissue lymphoma without disseminated disease may be feasible. We successfully used colonoscopic treatment without adjuvant therapy to treat early-stage pathogen-free colonic mucosa-associated lymphoid tissue lymphoma.

Bone Marrow Stromal Antigen 2 Is a Novel Plasma Biomarker and Prognosticator for Colorectal Carcinoma: A Secretome-Based Verification Study

Background. The cancer cell secretome has been recognized as a valuable reservoir for identifying novel serum/plasma biomarkers for different cancers, including colorectal cancer (CRC). This study aimed to verify four CRC cell-secreted proteins (tumor-associated calcium signal transducer 2/trophoblast cell surface antigen 2 (TACSTD2/TROP2), tetraspanin-6 (TSPAN6), bone marrow stromal antigen 2 (BST2), and tumor necrosis factor receptor superfamily member 16 (NGFR)) as potential plasma CRC biomarkers. Methods. The study population comprises 152 CRC patients and 152 controls. Target protein levels in plasma and tissue samples were assessed by ELISA and immunohistochemistry, respectively. Results. Among the four candidate proteins examined by ELISA in a small sample set, only BST2 showed significantly elevated plasma levels in CRC patients versus controls. Immunohistochemical analysis revealed the overexpression of BST2 in CRC tissues, and higher BST2 expression levels correlated with poorer 5-year survival (46.47% versus 65.57%; p = 0.044). Further verification confirmed the elevated plasma BST2 levels in CRC patients (2.35 ± 0.13 ng/mL) versus controls (1.04 ± 0.03 ng/mL) (p < 0.01), with an area under the ROC curve (AUC) being 0.858 comparable to that of CEA (0.867). Conclusion. BST2, a membrane protein selectively detected in CRC cell secretome, may be a novel plasma biomarker and prognosticator for CRC.

Sebacoyl Dinalbuphine Ester Extended-release Injection for Long-acting Analgesia: A Multicenter, Randomized, Double-blind, And Placebo-controlled Study in Hemorrhoidectomy Patients

Objectives: This study was conducted to evaluate the safety and efficacy of single sebacoyl dinalbuphine ester (SDE) injection (150 mg/2 mL) when administered intramuscularly to patients who underwent hemorrhoidectomy for postoperative long-acting analgesia. Methods: A total of 221 patients scheduled for hemorrhoidectomy from 6 centers in Taiwan were randomly divided into SDE group and placebo group, and received the treatment, vehicle or SDE, 1 day before the surgery. Visual analogue scale (VAS) was recorded up to 7 to 10 days. Pain intensity using VAS AUC through 48 hours after surgery was calculated as the primary efficacy endpoint. Results: Area under the curve of VAS pain intensity scores (VAS AUC) through 48 hours after hemorrhoidectomy was significantly less in SDE group than those in placebo group (209.93 vs. 253.53). VAS AUC from the end of surgical procedure to day 7 was also significantly different between SDE and placebo group (630.79 vs. 749.94). SDE group consumed significantly less amount of other analgesics, such as PCA ketorolac and oral ketorolac. Median time from the end of surgery to the first use of pain relief medication was also shortened in the placebo group than in the SDE group. Most adverse events were assessed as mild and tolerable in both groups. Discussion: SDE injection demonstrated an extended analgesia effect, with a statistically significant reduction in pain intensity through 48 hours and 7 days after hemorrhoidectomy.

S100P, a calcium-binding protein, is preferentially associated with the growth of polypoid tumors in colorectal cancer

Colorectal cancer (CRC) is a genetically heterogeneous disease with distinct morphological patterns. It has been shown that polypoid and ulcerative CRC displays different genetic alterations. In the present study, we aimed to investigate genes with differential expression patterns between ulcerative and polypoid CRC. cDNA microarray analysis was performed to compare the gene expression profiles in samples of ulcerative and polypoid CRC with paired normal mucosa samples. Potential candidate genes were further validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot analysis and immunohistochemistry. The epigenetic regulation of gene expression was investigated using methylation-specific PCR (MSP). cDNA microarray analysis identified 11 upregulated and 14 downregulated genes which were differentially expressed in samples from both tumor types compared to the matched normal mucosa samples. Among these, S100P was the only upregulated gene preferentially associated with polypoid CRC (P=0.032). The samples of polypoid CRC displayed significantly higher S100P protein and mRNA expression levels than the samples of ulcerative CRC (P<0.05, respectively). Using semi-quantitative immunohistochemical analyses, S100P overexpression was found to be preferentially associated with polypoid CRC (24/30 vs. 14/40, P<0.001). The relative methylation level determined by MSP did not differ significantly between the samples of polypoid and ulcerative CRC (43.36 vs. 49.10%, P=0.168), indicating that promoter hypomethylation was not directly related to the upregulation of S100P mRNA. Our results demonstrate that the upregulation of S100P mRNA and protein expression is a predominant characteristic in polypoid CRC, whereas ulcerative CRC presents with a wide range of expression levels, indicating that S100P overexpression is not a key determinant in conferring invasion properties. The clinicopathological significance of S100P in CRC requires further investigation in well-controlled studies.

Immunohistochemical study of vascular endothelial growth factor (VEGF) and matrilysin (MMP-7) in T1 adenocarcinoma of the colon and rectum to predict lymph node metastases or distant metastases.

BACKGROUND/AIMS Predicting the lymph node metastatic or distant metastatic potential of T1 adenocarcinoma of the colon and rectum remains a major challenge. We investigated the role of the expressions of tumor matrilysin (MMP-7), VEGF-C and VEGF-A in predicting these metastatic potentials. METHODOLOGY Single T1 adenocarcinomas were examined and pathological tumor factors were reviewed. Immunohistochemical staining of VEGF and MMP-7 was performed and the metastatic potential was defined on the basis of the presence of lymph nodes in the specimen or the identification of other distant metastasis during follow-up examinations. RESULTS There was little correlation between the IHC staining results of VEGF-A, VEGF-C and MMP-7 in the same specimen (kappa<0.1). After a 61-month median follow-up (2-131 months), 17 (11.8%) tumors showed metastatic potential, including 14 lymph node metastases and 3 distant metastases. The tumors showing high levels of MMP-7 expression had higher metastatic potentials than those with low expression (19.1% vs. 8.2%, respectively; p=0.057). Overexpression of MMP-7 generally indicated an inferior overall survival (p=0.09). In analysis of the traditional pathological tumor factors, only lymphovascular invasion showed significance in predicting metastatic potential (p=0.04). CONCLUSIONS Overexpression of MMP-7 generally indicated a higher metastatic potential and inferior overall survival. Lymphovascular invasion was a significant risk factor for lymph node metastasis.