Jeng-Fu You

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.

MicroRNA-223 and microRNA-92a in stool and plasma samples act as complementary biomarkers to increase colorectal cancer detection

Aberrant levels of circulating miRNAs are potential biomarkers for the early detection of colorectal cancer (CRC). However, no previous systematic study has examined miRNAs in various specimen types from the same patient to evaluate their clinical utility. In this study, we compiled information from ∼450 articles published before 2012, and selected the 46 most frequently reported CRC-related miRNAs as candidates. We then established a 46-miRNA multiplex RT-qPCR method, and efficiently examined two clinically accessible samples: stool from fecal occult blood test and EDTA plasma. A total of 62 tissue, 447 stool, and 398 plasma samples were collected from CRC patients and healthy controls. Good correlations of detectable miRNAs were noticed in paired tumor tissues, stool, and plasma samples of 62 CRC patients. Using these 62 CRC patients and 62 matched healthy controls as the training set, 5 and 11 differentially expressed miRNAs achieved the area under the ROC curve (AUC) greater than 0.7 in stool and plasma samples, respectively. The selected miRNAs was subsequently validated using the remaining enrolled samples as the test cohort; 4 miRNAs in stool and 6 miRNAs in plasma were maintained discriminating powers for CRC patients. After examining the complementary effect, combined analysis of miR-223 and miR-92a, which were commonly present in stool and plasma samples, yielded the highest sensitivity of 96.8% and the specificity of 75% for CRC (AUC = 0.907). These results allowed us to establish a two-miRNA biosignature in two types of CRC clinical specimens with a high sensitivity for CRC detection.

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.

PTPRT and PTPRD Deleterious Mutations and Deletion Predict Bevacizumab Resistance in Metastatic Colorectal Cancer Patients

Background: Bevacizumab-based regimens are used as standard treatments for colorectal cancer. Unfortunately, there are no established predictive markers for bevacizumab response. Methods: Tumor samples from 36 metastatic colorectal cancer patients treated with bevacizumab plus chemotherapy were analyzed by next-generation sequencing of all coding exons of more than 400 genes. Single gene and signaling pathway analyses were performed to correlate genomic data with response. Results: Among the genes most frequently mutated in our cohort, only mutations in PTPRT, a phosphatase involved in JAK/STAT signaling, were associated with response status, with deleterious mutations being enriched in non-responders. Pathway analysis revealed that deleterious mutations in genes of the JAK/STAT pathway, namely in PTPRT and the related gene PTPRD, correlated with resistance. Mutations in RTK/PI3K/RAS, Wnt and TGFβ pathways did not associate with response. Lack of response was observed in all patients with deleterious mutations or copy number loss of PTPRT/PTPRD (n = 10), compared to only 30.8% (n = 8) of patients without such alterations (relative risk, 3.25; 95% CI, 1.83–5.79, p = 0.0003). Similarly, PTPRT/PTPRD deleterious alterations were associated with shorter progression-free survival, an association that was retained in multivariate analysis (HR, 3.33; 95% CI, 1.47–7.54; p = 0.0038). Conclusion: Deleterious alterations in PTPRT/PTPRD are potential biomarkers for bevacizumab resistance.

Impact of Diabetes Status on Long Term Oncological Outcome of Stage II Colorectal Cancer

目的 糖尿病與大腸直腸癌有相似的飲食及生活因子。目前許多研究均顯示糖尿病病患有較高的大腸直腸癌發生率及較差的總存活率，但是長期存活率及癌症相關存活率的研究卻相對有限且無一致的結論。方法 挑選本院1999 年至2002 年第二期大腸直腸癌接受根除性切除但排除接受放射治療之病患。比較糖尿病及非糖尿病病患之臨床病理表現、長期總存活率及癌症相關存活率，另外則比較不同糖尿病治療方式之癌症相關存活率之異同。結果 在大腸直腸癌病患中，罹患糖尿病的病患有較高的年齡、BMI、慢性腎衰竭 (19%vs. 7.5%, p ＜ 0.001)、心肌梗塞 (16.7% vs. 5.7%, p = 0.043)、心衰竭病史 (4.8% vs. 1.2%, p= 0.008) 及癌胚抗原數值 (CEA ＞ 5 ng/ml, 55.2 vs. 33.6%, p ＜ 0.001)。兩組間總體存活率並無顯著差異，但糖尿病病患比非糖尿病病患有顯著較高的5 年癌症相關存活率 (91%vs. 81%, p = 0.025) 及3 年疾病無復發率 (88% vs. 78%, p = 0.015)。在多變數分析中排除metformin 使用及其他因子後糖尿病仍有顯著較低之疾病復發率風險 (HR = 0.192, p =0.023)，然而多變數分析中糖尿病之癌症死亡率風險卻達邊緣性統計顯著 (HR = 0.258, p= 0.064)。結論 糖尿病在第二期大腸直腸癌病患中雖有較高的癌胚抗原值，但排除metformin 使用後糖尿病對於第二期大腸直腸癌之癌症預後為明顯保護因子。

Reasonable Follow Up Interval of Colonoscopy for Resected Stage I Colorectal Cancer Patient

目的 目前針對第一期大腸癌術後的病人，對於追蹤的準則並沒有統一的共識。在我們的研究中，我們嘗試著去尋找關於異時性大腸癌的嚴重程度的危險因子，以及合理的大腸鏡追蹤時間間格。方法 從1995 年1 月到2015 年12 月，在台灣林口長庚醫院總共有17025 個病人被診斷大腸癌，其中有2258 位病人是第一期並且接受治癒性手術。在之後的追蹤裡，我們總共發現了31 個病人有異時性大腸癌做進一步的分析。結果 在我們的資料庫裡，異時性大腸癌的嚴重度跟家族癌症史、年齡、性別、合併症如高血壓心臟病及糖尿病、第一次切除大腸癌時的CEA 數值、切除方式、T1 或T2、以及原始大腸癌的位置沒有統計學上顯著的相關。結論 大腸鏡追蹤的時間間格跟異時性大腸癌的嚴重程度有顯著相關，並且我們算出一條回歸曲線，根據這條曲線方程式，我們可以預測如果預期在發現異時性大腸癌時仍在可治癒的程度 (第三期以內)，合理的大腸鏡追蹤間格為75 個月。

Neoadjuvant Long Course CCRT Significantly Increases Disease Free Survival among Pathological Stage III Rectal Cancer Patients as Compared to Short Course RT Alone

目的 對於局部晚期直腸癌的病患，為了達到更好的局部控制及存活率，無論是術前短程放射治療或是長程同步放化療皆被使用中。然而，如何選擇這兩個治療方法仍無定論。方法 我們蒐集了2002 年1 月1 日至2006 年12 月31 日於林口長庚醫院診斷為局部晚期直腸癌的病患，所有病患皆接受完整術前短程放射治療或是長程同步放化療並接受根除性手術，術後追蹤日期至2009 年12 月31 日。變異項目如病患的性別、年齡、術前CEA 濃度及腫瘤位置皆被收集分析。總生存率，無病生存率，局部復發率和遠處轉移率也由統計分析比較。結果 在臨床病理特徵方面，腫瘤位置是短程治療及長程治療唯一的差異項 (低位直腸63.4% vs. 81.0%, p = 0.049)。針對淋巴結轉移與否的次族群分析存在許多統計上的差異。對於沒有淋巴結轉移的次族群，短程治療有較好的總生存率 (五年存活率89.3% vs. 62.2,p = 0.009)。對於有淋巴結轉移的次族群，長程同步放化療則有較好的無病生存率 (五年存活率27.8% vs. 64.7%, p = 0.018)，較低的遠處轉移率 (Metastasis free rate 26.8% vs.76.5%, p = 0.003) 及趨向有較好的總生存率 (p = 0.059)。對於局部復發率，兩者並無顯著差異 (83.0% vs. 87.5%, p = 0.557)。結論 基於我們的研究，對於中低位直腸癌且有淋巴結轉移的病患，為了達到更好的無病生存率，術前長程同步放化療是可以考慮的治療方式。對於沒有淋巴結轉移的病患，術前短程放療則與術前長程同步放化療有同樣的疾病控制。

Prognosis of the Neuroendocrine Tumors of the Colon and Rectum with Lymph Node Metastasis after Surgical Treatment with or without Adjuvant Therapy

Purpose. Neuroendocrine tumor (NET) of the colon and rectumis rare and is different from the way of treatment of the so-called colorectal cancer. The treatment of the NET of the colon and rectum is mainly based on the endoscopic or surgical resection. However, the adjuvant therapy beyond the resection to the advanced disease is still not standardizedand there is little evidence discussion about it. Theaim of the study is to review the outcome of the advanced neuroendocrine tumor of the colon and rectum with or without adjuvant therapy in two medical centers in Taiwan. Methods. From 1995 to 2015, a totalof seventeen patients with NET of the colon and rectum with lymph node metastasis without distant metastasis were enrolled in this case serie. The clinical symptoms, lab data, pathology result and treatment were reviewed and disease survival was obtained for further evaluation. Results. In 2010, WHO divided the NET into three categories according to the cell proliferation by the pathology. In our case series (NET of the colon and rectum with lymph node metastasis, TMN stage IIIb), the disease survival is correlated with the WHO 2010 classification (p ＜ 0.001). Others factors including T stage, adjuvant therapy, location of the NET have no significance difference between the disease survivals. Conclusion. NET of the colon and rectum is rare and the prognosis of tumor with lymph node metastasis after surgical treatment depends on the 2010 WHO classification according to the tumor cell differentiation. There is no apparent benefit from adjuvant therapy after surgical treatment with curative intent in our case series. Further case collection and a prospective study are needed to confirm the treatment options of NET of the colon and rectum.