Ming-Jer Huang

Molecular analysis of secondary kinase mutations in imatinib-resistant gastrointestinal stromal tumors

Most gastrointestinal stromal tumors (GISTs) are associated with activating kinase mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene, and imatinib has revolutionized the care of advanced GISTs. However, most patients gradually developed resistance to imatinib. We intend to identify the secondary kinase mutations in imatinib-resistant GISTs and to study the relationship between secondary kinase mutations and the clinical response to imatinib. Twelve advanced GIST patients, who have developed resistance to imatinib were included in this study. Paraffin-embedded pretreatment GIST specimens and progression lesions of the tumors after resistance to imatinib were analyzed for kinase mutations in exons 9, 11, 13, and 17 of KIT gene and exons of 10, 12, 14, and 18 of PDGFRA gene. Primary KIT mutations have been found in all but one of the primary tumors including one case harboring de novo double KIT exon 11 mutations. Secondary kinase mutations in KIT and PDGFRA were found in seven and 1 of 12 patients, respectively. Two patients harbored more than one secondary KIT mutations in different progression sites, and there are four types of clonal or polyclonal evolution being observed. The secondary PDGFRA exon 14 mutation H687Y is a novel mutation that has never been reported before. Acquired secondary kinase mutations are the most important cause of secondary imatinib resistance in advanced GISTs. The identification of secondary kinase mutations is important in the development of new therapeutic strategies.

Neurofibromatosis with gastrointestinal stromal tumors: insights into the association.

The frequent association of stromal tumors with neurofobromatosis raises high suspicion of a possible correlation between the two entities. The aim of this study was to analyze clinicopathologic features of patients with concomitant neurofibromatosis and gastrointestinal stromal tumors and to discuss the molecular basis for their possible pathogenesis. Detailed information about clinical presentation, histology, immunostains, polymerase chain reaction amplification, and sequencing in three of our own cases was obtained. Stromal tumors presented with abdominal pain in one case and hemorrhage in another. One patient underwent surgery for malignant transformation of neurofibroma and stromal tumors were found incidentally. Stromal tumors were consistently positive for CD117, while the malignant peripheral sheath tumor was not. Mutation in the KIT juxtamembrane domain was found in one case. In this respect, some stromal tumors lack demonstrable KIT mutations but KIT remains activated. We reasoned that other mechanisms, like the Ras pathway involved in neurofibromatosis type 1, might play a role in KIT activation.

Clinical outcome of primary gastric lymphoma treated with chemotherapy alone or surgery followed by chemotherapy.

BACKGROUND The role of surgical resection in the treatment of primary gastric lymphoma (PGL) remains unclear. This retrospective study evaluated the clinical outcome of PGL treated with chemotherapy alone or surgery followed by chemotherapy. METHODS During 1986-2003, 59 patients with PGL (other than mucosa-associated lymphoid tissue type lymphoma) were identified from hospital files. The medical records, pathologic sections, radiographic images and treatment modalities of these patients were reviewed. Patients were categorized into localized (stage IE and IIE-1) and advanced (stage IIE-2 or beyond) stage groups. Survival was estimated by the Kaplan-Meier method. RESULTS The study included 55 patients who received treatment at the same institute. Among them, 32 had localized PGL (15 stage IE, 17 stage IIE-1) and 23 had advanced disease. The median survival of the localized stage group was not reached during a mean follow-up of 168.1 +/- 16.7 months (95% confidence interval [CI], 135.4-200.8 months), while that of the advanced stage group was 33.0 +/- 6.8 months (95% CI, 19.7-46.5; p < 0.001, log-rank test). Among patients with localized PGL, the 5-year overall survival rate of those receiving chemotherapy alone (n = 19) or combination therapy (surgery followed by chemotherapy, n = 13) was 73.4% and 87.5%, respectively (p = 0.229). The 5-year disease-free survival was 68.4% and 84.6%, respectively (p = 0.540). However, post-chemotherapy life-threatening hemorrhage occurred in five of the 32 patients (15.6%) in the localized stage group: four in the chemotherapy-alone group, and one in the combination therapy group, all of whom had failed to achieve complete response. CONCLUSION The clinical outcome of localized PGL treated by chemotherapy alone is similar to that treated by surgery followed by chemotherapy in terms of tumor response, disease-free survival and overall survival, suggesting that surgery be reserved for those with residual tumors after chemotherapy.

Clinical implications of C-kit gene mutation in patients with large gastrointestinal stromal tumors

Background and Aim:  To evaluate the clinical implications of C‐kit gene mutation in patients with gastrointestinal stromal tumors (GIST) greater than 10 cm in size.

Combined thalidomide and interferon-? for chronic hepatitis C-related hepatocellular carcinoma

Successful treatment with the combination of low dose thalidomide and interferon‐α is described in an 89‐year‐old man who had chronic hepatitis C‐related metastatic hepatocellular carcinoma. Thalidomide 100 mg/day and interferon‐α2b 3 million units/week were prescribed. After 9 months of the combination therapy, his serum α‐fetoprotein level had declined from 24 549 ng/mL to less than 2.76 ng/mL. The recurrent liver tumors decreased in size and the metastatic lung lesions had complete remission after treatment. Combination therapy with lower dose interferon‐α and thalidomide, two antiangiogenic drugs with different mechanisms of action, was associated with a good response and was well tolerated in this preliminary study.

Is extramedullary plasmacytoma an oligoclonal tumour with clonal selection during tumour progression

rare malignant neoplasms that histologically contain both epithelial and stromal components. Such lesions are more frequently encountered in the uterus, but have been reported in the ovary. The stromal component may contain rhabdomyosarcoma, fibrosarcoma, or other homologous or heterologous elements. Several features of our case argue against this diagnosis. First, these tumours typically occur in postmenopausal women. The epithelial component of most ovarian carcinosarcomas are endometrioid or serous adenocarcinoma rather than a transitional-type epithelium. Finally, the lack of significant cytological atypia or proliferative activity in the epithelium makes carcinosarcoma unlikely. Determination of malignant potential in Brenner tumours usually focuses on assessing the degree of cytological atypia within the epithelial component. This case suggests that, in rare instances, sarcoma can develop within the stromal proliferation associated with these tumours. To the best of our knowledge, this case represents a unique histological presentation which has not heretofore been described.

The Clinical Significance of CD117(c-kit) in Gastrointestinal Stromal Tumors

The term gastrointestinal stromal tumor (GIST) has been used to refer to the largest group of mesenchymal tumors in the gastrointestinal tract. Recent studies have demonstrated the presence in most GISTs of c-kit gene mutations that cause activation of a c-kit tyrosine kinase. The c-kit proto-oncogene protein is identfied by an immunohistochemical stain positive for CD117. GISTs have now been reclassfled so that cell-surface expression of CD117 is required for diagnosis. STI 571, an inhibitor of the kinase domain of c-kit is a newly developed therapy for GIST. We reviewed 95 cases of GI tract stromal tumors diagnosed by pathology between October 1992 and November 2002 in a single medical center. We performed immunohistochemical staining for CD117, CD34, SMA and S-100 on those specimens. The patients were grouped according to the results of the CD117 immunostaining, and the groups were compared for characteristics and survival. We also analyzed factors associated with prognosis in the CD117 positive group. Of the 95 cases, CD117 immunostaining was positive in 81 cases (85.2%) and negative in 14 (14.8%). Factors associated with a positive CD117 immunostain were male sex, gastric tumors, and a positive CD34. There was no sign (ficant difference in the survival of patients with and without CD117 (68.9 months vs. 59.3 months, F＞0.05). Significant risk factors for a poor prognosis in the group positive for CD117 included tumor size＞5cm, limited resectability, metastasis, or recurrence. In conclusion, immunostaining for CD117 has provided a new definition of GIST, separating these tumors from others of mesenchymal origin. However, in our experience, survival was not influenced by whether the tumor was positive or negative for CD117. Tumor size and tumor metastasis are the most important prognostic factors of survival in our series.

Therapeutic Effect of Arsenic Trioxide Containing Lotion in a Human Bladder Carcinoma Xenograft Model

BACKGROUND: Patients with metastatic carcinoma develop cutaneous metastases in about 10% of cases. These skin metastatic lesions are usually treated by radiation therapy and/or chemotherapy with disappointing results. In this study we used human bladder carcinoma xenograft nuice as a model to investigate whether arsenic trioxide lotion has an anti-tumor effect on skin metastases of human solid tumor cells. MATERIALS AND METHODS: Female BALB/c-Hfbllnu mice received subcutaneous injection to the left flanks on day 0 with 2×10^6 viable HTB-9 tumor cells. When the mean tumor size reached 7-8mm at the 19(superscript th) day, the mice were randomly divided into three groups of six mice. The first group was treated with the lotion containing no arsenic trioxide and served as the control group. The second group were given artificial wounds on tumors which were then treated with arsenic trioxide lotion. The third group was treated with the arsenic trioxide lotion on tumors. The treatment schedule was three times a week. The total dose of each treatment was 0.14gm lotion (containing 0.0462mg arsenic trioxide), which was applied to the skin over each visible tumor. RESULTS: There was a significant difference (P＜0.05) in tumor growth between group 1 and group 2, and between group 1 and group 3 beginning from the 35(superscript th) day after treatment, but there was no significant difference between group 2 and group 3. Arsenic trioxide lotion treatment delayed the growth of the subcutaneous bladder carcinoma regardless of whether the tumor was covered by skin or artificially wounded. CONCLUSION: The results of this study suggest that arsenic trioxide lotion is a worthy candidate for clinical trials.