Hsin-Yuan Hung

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.

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.

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.

Abdominopelvic Actinomycosis-Treatment Outcomes at the Chang Gung Memorial Hospital during the Past 16 years

Purpose. Actinomycosis is uncommon and it causes various clinical pictures mimicking cancer, inflammatory disease, or diverticulitis, along with rarity of the disease, the diagnosis of actinomycosis is be difficult. We draw out the optimal treatment modalities for the abdominopelvic action-mycosis in addition to proposed medical management (high-dose penicillin for a long and variable interval, 6 months to 1 year) or combined surgery with antibiotics treatment. Methods. We review the previous cases of actinomycosis in the abdomen and pelvis. They were recruited from 1984 through 2001 at Division of Colon and Rectal Surgery, Department of Surgery in the Chang Gung Memorial Hospital (CGMH). Reviewing the charts, we recorded the clinical manifestations, image findings, white blood cell counts (WBC) and differential counts, surgical procedures, post-operative antibiotics treatment duration, interval of follow-up, and history of IUD use. Results. In our series, the median follow-up period was 16 months (6-153 months). Eight patients (cases 1, 2, 4, 5 and 7-10) underwent radical surgery because the disease was mimicking malignancy morphologically and two patients (case 3 and 6) received prolonged antibiotic treatments after biopsy and bypass. Prolonged antibiotic treatments after radical resection of the lesions were not routine. No relapse even no prolonged antibiotics treatment during follow-up was identified. Conclusion. In our cases, the standard long-term antibiotic treatment could be used in patients having no radical resection. But close follow-up by CT and clinical examination are important in such cases because disease relapse is possible. Surgical intervention alone can cure cases with infection by complete removal of the infection foci, and long-term antibiotic therapy is unnecessary.

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。