Peng Chan Lin

The Prognostic Significance of RON and MET Receptor Coexpression in Patients with Colorectal Cancer

PurposeAlthough Recepteur d’Origine Nantais (RON), a member of the MET receptor tyrosine kinase family, is overexpressed and constitutively active in some primary tumors and tumor cell lines, its expression pattern and clinical significance in colorectal cancer are not well documented.MethodsBy using immunohistochemical staining, we examined RON and MET expression in 135 colorectal cancer specimens and investigated the association of the immunoreactivity of both receptors with colorectal cancer clinical parameters and prognosis.ResultsWe found moderate to strong expression in 99 cases (73 percent) for RON and 97 cases (72 percent) for MET. Univariate analysis showed that increased immunoreactivity of RON or MET was associated with shorter patient survival and that moderate to strong coexpression of both receptors was associated with a significantly worse prognosis. Multivariate Cox analysis showed that the risk of tumor recurrence for patients with high-RON/high-MET expression was approximately 11 times greater than for patients with low-RON/low-MET expression (P = 0.001). In addition, RON and MET expression levels were positively correlated (P ≤ 0.001; τ = 0.306).ConclusionsThe crosstalk between RON and MET in colorectal cancer seems important. Evaluating the expression patterns of RON and MET was predictive of clinical outcome for patients with colorectal cancer.

Fatal Fulminant Hepatitis B after Withdrawal of Prophylactic Lamivudine in Hematopoietic Stem Cell Transplantation Patients

Hepatitis B virus (HBV) reactivation can give rise to acute hepatitis and even fatal fulminant hepatitis in patients receiving immunosuppressive or cytostatic treatment. Recently, the prophylactic use of lamivudine for HBV reactivation in HBV surface antigen-positive chronic-disease patients undergoing hematopoietic stem cell transplantation (HSCT) has been reported. However, the appropriate duration for this prophylactic therapy is unclear. Here, we report 2 cases of fatal fulminant hepatitis B reactivation in HSCT patients after lamivudine withdrawal. One patient with non-Hodgkin’s lymphoma completed 6 courses of CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisone) and autologous peripheral blood SCT (PBSCT). Lamivudine was discontinued 3 months after transplantation. The second patient had acute myeloid leukemia. He received induction chemotherapy and postremission allogeneic PBSCT as late intensified consolidation therapy. Lamivudine treatment was discontinued 10 months after transplantation. In both patients, HBV reactivation 2 to 3 months following lamivudine cessation led to fatal fulminant hepatitis. We suggest that the duration of prophylactic use of lamivudine in chronic HBV carriers receiving HSCT be prolonged until the patient’s immune system has been reconstituted.

A phase II study of weekly docetaxel and cisplatin plus oral tegafur/uracil and leucovorin as first-line chemotherapy in patients with locally advanced or metastatic gastric cancer

Background:Docetaxel plus cisplatin and 5-fluorouracil has become a new standard for treating advanced gastric cancer. However, high rates of severe neutropenia limit its application. Modification of the regimen could be the solution to get similar activity but less myelosuppression.Methods:Patients with histologically confirmed, locally advanced, or recurrent/metastatic gastric adenocarcinoma without previous chemotherapy were enrolled. This regimen consisted of docetaxel (Tyxan, TTY, Taipei, Taiwan) 30-min infusion at a dose of 36 mg m−2, followed by cisplatin 30 mg m−2 infusion over 1 h on days 1 and 8, and oral tegafur/uracil 300 mg m−2 per day plus leucovorin 90 mg per day on days 1–14, every 3 weeks. Tumour response was evaluated after every 2 cycles of treatment.Results:From August 2007 to March 2009, 45 patients were enrolled. The median age was 56 years (range: 22–75). Among the 40 patients evaluable for tumour response, one achieved a complete response, 22 had partial responses and 11 had stable disease. The overall response rates of the evaluable and intent-to-treat (ITT) populations were 58% (95% CI: 41–74%) and 53% (95% CI: 38–68%), respectively. The disease control rates in these populations were 85% (95% CI: 70–94%) and 82% (95% CI: 68–92%), respectively. In the ITT analysis, the median time to progression and overall survival were 6.8 and 13.9 months, respectively. Major grade 3–4 toxicities were neutropenia (51%), anaemia (22%), diarrhoea (16%), and infections (20%). No patient died of treatment-related toxicities.Conclusion:Concurrent weekly docetaxel and cisplatin plus oral tegafur/uracil and leucovorin are effective and well tolerated in the treatment of advanced gastric cancer.

Acute polymyositis after donor lymphocyte infusion.

Abstract:  Polymyositis usually occurred along with other manifestations of chronic graft‐versus‐host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) had been reported. However, polymyositis with a sole manifestation of acute GVHD following donor lymphocyte infusion (DLI) is rare. We reported a 45‐yr‐old man of acute lymphoid leukemia post‐allogeneic HSCT 6 months developed acute polymyositis after DLI. He did not develop any symptoms, signs of acute or chronic GVHD following allogeneic HSCT, despite withdraw of immuosuppresive agents, cyclosporin A (CsA). As the DNA‐STR of bone marrow analysis showed mixed chimerism, he received the DLI for remission on May 16, 2002. Acute polymyositis developed following DLI 22 d later. The clinical presentation of polymyositis is compatible with a manifestation of acute GVHD following DLI. It also responds to the treatment of steroid and CsA.

Cyclooxygenase-2 expression in the tumor environment is associated with poor prognosis in colorectal cancer patients

The development of colorectal cancer (CRC) is commonly accompanied by the overexpression of the cyclooxygenase-2 (COX-2) gene, with high levels being most common in early colorectal lesions. In the present study, we hypothesized that the expression of COX-2 in normal mucosa affects the expression of COX-2 in adjacent tumors. COX-2 protein expression levels were determined in tumor tissues and the adjacent normal mucosa of 49 paired clinical CRC specimens using western blotting and immunohistochemistry (IHC) staining. The majority of specimens exhibited an extremely low level of COX-2 expression in the tumor tissue and a markedly higher expression level in the adjacent normal tissue, however, high COX-2 expression in the tumor was shown to correlate with a high recurrence rate and poor overall survival. Of the nine CRC cell lines, HT29 showed consistently higher levels of COX-2 expression. Therefore, COX-2 expression in the normal tissue adjacent to the tumor may be involved in the tumorigenesis of CRC. These observations are likely to be useful in determining the significance of COX-2 expression in the tumorigenesis of CRC.

High prevalence of SV40 infection in patients with nodal non-Hodgkin's lymphoma but not acute leukemia independent of contaminated polio vaccines in Taiwan

Recent studies have linked simian virus 40 (SV40) to non-Hodgkins lymphoma (NHL), especially in countries in which people were exposed to contaminated polio vaccines prior to 1963. In Taiwan, nearly all children were not exposed to contaminated polio vaccine during this period; the relationship between SV40 infection and hematological malignancies is unclear and deserves to be studied. Using PCR amplification of SV40 large T antigen DNA, confirmed by Southern blot hybridization and sequence analysis, 91 frozen lymph nodes from NHL patients were examined. Thirteen (14.3 percent) showed positive for SV40. All other test samples, including diagnostic bone marrow from patients with acute leukemia, peripheral blood from 10 relatives of SV40 positive-patients and 91 age-matched normal volunteers, and 5 reactive hyperplastic lymphoid tissues, showed negative. These results may reflect that human-to-human transmission of SV40 is independent of contaminated polio vaccines; and SV40 is possibly associated with the development of NHL in Taiwan (p = 0.0001). Prospective studies are needed to determine the prevalence of SV40 infections in our and other human populations and to explore the means of transmission of the virus.

Comparison of Myeloablative and Nonmyeloablative Hematopoietic Stem Cell Transplantation for Treatment of Chronic Myeloid Leukemia

This retrospective study compared outcomes for 81 chronic myeloid leukemia patients who underwent myeloablative or nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT). Sixty-five patients received myeloablative HSCT, and 16 patients received fludarabine (Fd), low-dose busulfan (Bu), and antithymocyte globulin (ATG) in nonmyeloablative HSCT. We determined overall survival (OS) and disease-free survival (DFS), as well as the occurrence of acute and chronic graft-versus-host disease (GVHD).The incidences of acute GVHD of grades II to IV were 14.0% and 18.7% for the myeloablative and nonmyeloablative groups, respectively. The incidence of chronic GVHD was significantly higher in the nonmyeloablative group (80% versus 66%). Five-year OS and DFS rates were significantly higher in nonmyeloablative group (70% for both), compared with 56% and 54%, respectively, for the myeloablative group. A univariate analysis, however, revealed a strong but statistically insignificant trend for enhanced overall OS and DFS in the nonmyeloablative group (P = .1 and .07, respectively). A multivariate analysis with the factors of treatment, age, sex, acute and chronic GVHD, and disease status at the time of transplantation revealed that both OS and DFS were significantly higher in the nonmyeloablative group than in the myeloablative group. These findings suggest that nonmyeloablative Fd/Bu/ATG treatment is at least not inferior (and quite probably superior) in terms of patient outcome compared with standard myeloablative therapy. Further larger-scale randomized clinical trials are warranted to clarify the efficacy of this treatment regimen.

Differences in the frequencies of K-ras c12-13 genotypes by gender and pathologic phenotypes in colorectal tumors measured using the allele discrimination method

The frequencies of different genotypes of the K‐ras oncogene in colorectal cancer (CRC) reveal complex relationships among gender, age, and tumor aggression, however, differences among these studies could also be attributed to a lack of standardization of the detection methods used. We developed the allele discrimination assay, which uses dual‐color real‐time polymerase chain reaction (qPCR) as a fast K‐ras genotyping method, and demonstrated higher sensitivity and specificity than DNA sequencing with formalin‐fixed paraffin tissues. The assay detected K‐ras mutations among 83 of 204 patients with CRC (40.7%); 20.6% of these mutations were G12D (GAT) mutations, 7.4% were G13D (GAC) and G12V (GTT), and 5.3% were other types. A higher proportion of females was observed overall in tumors with K‐ras mutations (60.2%, P = 0.01), codon 12 mutations (63.2%, P = 0.005), and transversions (69.6%, P = 0.02), which reflected the higher prevalence of females among the well‐ to moderately differentiated tumors (29% in males vs. 53% in females; interaction P = 0.03). The opposite was observed for poorly differentiated tumors (47% in males vs. 35% in females). No significant influence of age was found on the prevalence of K‐ras mutation. Males with pathological changes and females with poorly differentiated tumors displayed GAT as a less common genotype compared with most other prevalence studies. In conclusion, allele discrimination, with no additional amplification step, is a fast and reliable genotyping method for detecting K‐ras c12–13 mutations. Using this method, we demonstrate differences in the frequencies of K‐ras genotypes by gender and pathologic phenotypes of CRC. Environ. Mol. Mutagen., 2012.

Routine defunctioning stoma after chemoradiation and total mesorectal excision: a single-surgeon experience.

AIM To investigate the 10-year results of treating low rectal cancer by a single surgeon in one institution. METHODS From Oct 1998 to Feb 2009, we prospectively followed a total of 62 patients with cT2-4 low rectal cancer with lower tumor margins measuring at 3 to 6 cm above the anal verge. All patients received neoadjuvant chemoradiation (CRT) for 6 wk. Among them, 85% of the patients received 225 mg/m(2)/d 5-fluorouracil using a portable infusion pump. The whole pelvis received a total dose of 45 Gy of irradiation in 25 fractions over 5 wk. The interval from CRT completion to surgical intervention was planned to be approximately 6-8 wk. Total mesorectal excision (TME) and routine defunctioning stoma construction were performed by one surgeon. The distal resection margin, circumferential resection margin, tumor regression grade (TRG) and other parameters were recorded. We used TRG to evaluate the tumor response after neoadjuvant CRT. We evaluated anal function outcomes using the Memorial Sloan-Kettering Cancer Center anal function scores after closure of the defunctioning stoma. RESULTS The median distance from the lower margin of rectal cancer to the anal verge was 5 cm: 6 cm in 9 patients, 5 cm in 32 patients, 4 cm in 10 patients, and 3 cm in 11 patients. Before receiving neoadjuvant CRT, 45 patients (72.6%) had a cT3-4 tumor, and 21 (33.9%) patients had a cN1-2 lymph node status. After CRT, 30 patients (48.4%) had a greater than 50% clinical reduction in tumor size. The final pathology reports revealed that 33 patients (53.2%) had a ypT3-4 tumor and 12 (19.4%) patients had ypN1-2 lymph node involvement. All patients completed the entire course of neoadjuvant CRT. Most patients developed only Grade 1-2 toxicities during CRT. Thirteen patients (21%) achieved a pathologic complete response. Few post-operative complications occurred. Nearly 90% of the defunctioning stomas were closed within 6 mo. The local recurrence rate was 3.2%. Pathologic lymph node involvement was the only prognostic factor predicting disease recurrence (36.5% vs 76.5%, P = 0.006). Nearly 90% of patients recovered sphincter function within 2 year after closure of the defunctioning stoma. CONCLUSION Neoadjuvant CRT followed by TME, combined with routine defunctioning stoma construction and high-volume surgeon experience, can provide excellent surgical quality and good local disease control.

Dynamic change of tetraspanin CD151 membrane protein expression in colorectal cancer patients.

Purpose: To measure the CD151 expression in colorectal cancer (CRC). Methods: CD151 expression was assessed in 179 CRC patients and 39 patients with hepatic liver metastasis. Results: High CD151 expression was observed in 48% of patients with early-stage CRC versus only 33% of patients with metastatic colon cancer. A higher level of tumor invasion status correlated with a decrease in CD151 expression. Metastatic stage and advanced tumor stage correlated with a decreased CD151 expression. Twenty-seven out of the 39-paired samples had high CD151 expression in liver metastasis sites. Conclusions: CD151 expression is decreased in patients with metastatic CRC.