Chen Yuan Lin

ADAM9 promotes lung cancer metastases to brain by a plasminogen activator-based pathway.

The transmembrane cell adhesion protein ADAM9 has been implicated in cancer cell migration and lung cancer metastasis to the brain, but the underpinning mechanisms are unclear and clinical support has been lacking. Here, we demonstrate that ADAM9 enhances the ability of tissue plasminogen activator (tPA) to cleave and stimulate the function of the promigratory protein CDCP1 to promote lung metastasis. Blocking this mechanism of cancer cell migration prolonged survival in tumor-bearing mice and cooperated with dexamethasone and dasatinib (a dual Src/Abl kinase inhibitor) treatment to enhance cytotoxic treatment. In clinical specimens, high levels of ADAM9 and CDCP1 correlated with poor prognosis and high risk of mortality in patients with lung cancer. Moreover, ADAM9 levels in brain metastases derived from lung tumors were relatively higher than the levels observed in primary lung tumors. Our results show how ADAM9 regulates lung cancer metastasis to the brain by facilitating the tPA-mediated cleavage of CDCP1, with potential implications to target this network as a strategy to prevent or treat brain metastatic disease.

Prognostic impact of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with internal tandem duplication of FLT3

The FLT3 gene with internal tandem duplication (ITD) is a poor prognostic factor in patients with acute myeloid leukemia (AML), and the efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) for AML patients with FLT3-ITD is controversial. We examined 122 AML patients; 34 patients had FLT3-ITD and 39 patients received allogeneic HSCT. The median overall survival (OS) of patients with wtFLT3/nonHSCT, wtFLT3/HSCT, FLT3-ITD/nonHSCT and FLT3-ITD/HSCT was 40.7 months, 53.4 months, 9.8 months and not reached, respectively (p=0.006). Compared to the wtFLT3/nonHSCT patients, the hazard ratio (95% CI) of OS for wtFLT3/HSCT, FLT3-ITD/nonHSCT and FLT3-ITD/HSCT was 1.39 (0.61-3.18), 3.57 (1.58-8.10) and 0.40 (0.11-1.59), respectively, after adjustment of age, sex, WBC, LDH, karyotype, NPM, and FAB classification. This result indicated that patients with FLT3-ITD/nonHSCT had a significantly worse outcome, but allogeneic HSCT improved the prognosis for patients with FLT3-ITD.

Pretreatment metabolic tumor volumes to predict the short-term outcome of unresectable locally advanced squamous cell carcinoma of the esophagus treated with definitive chemoradiotherapy

PurposeThe aim of the study was to investigate the predictive role of pretreatment metabolic tumor volume (MTV) in patients with squamous cell carcinoma of locally advanced esophageal cancer treated with definitive chemoradiotherapy. Patients and methodsNinety patients received pretreatment with 18F-fluorodeoxyglucose (18F-FDG) PET/CT, and two types of MTVs were measured on the basis of either a maximal standardized uptake value (SUVmax) of 2.5 (MTV2.5) or a fixed threshold of 20% (MTV20%). Overall survival (OS) and disease-free survival (DFS) were examined, and independent prognosticators were identified by Cox regression analysis. ResultsOn a median follow-up of 15 months, 51 patients were seen to have died because of tumor recurrence or other illnesses. Multivariate analysis of OS revealed that MTV20%>40 ml was the only predictor of outcome with a lower 1-year OS [P=0.003, hazard ratio (HR)=2.29, 95% confidence interval (CI) 1.36–3.91]. Two independent predictors of DFS were MTV20%>40 ml (P=0.02, HR=1.78, 95% CI 1.09–2.91) and stage IV disease (P=0.01, HR=1.84, 95% CI 1.12–3.03). ConclusionPretreatment MTV20% is a novel marker for OS and DFS in patients with unresectable locally advanced esophageal cancer treated with definitive chemoradiotherapy. Treatment intensification must be considered for patients with higher MTVs.

Kinetics of T helper subsets and associated cytokines correlate well with the clinical activity of graft-versus-host disease.

Background CD4+interferon (IFN)-γ+ T cell (Th1) and CD4+interleukin (IL)-4+ T cell (Th2) polarizations are crucial in the pathogenesis of graft-versus-host disease (GVHD). However, this hypothesis is largely based on animal experiments of Parent-into-F1 GVHD model. The causal relationship between kinetics of Th1, Th2 and associated cytokines and the clinical activity of GVHD in a real world situation remains unknown. Methodology Peripheral blood was collected every week prospectively from Day 0 to Day 210 (patients without GVHD) or Day 300 (patients with chronic GVHD) after allogeneic peripheral blood stem cell transplantation in consecutive 27 patients. The frequencies of Th1 and Th2 within CD4+ T cells were determined by flow cytometry and pplasma IFN-γ, IL-12, IL-4, and IL-10 were determined by ELISA. Principal Findings Kinetics of Th1, Th2 frequency, and the plasma IL-10 and IFN-γ more commonly coincided with, rather than predicted, the activity of GVHD. These markers are significantly higher when acute or chronic GVHD developed. The kinetics of IL-10 is especially correlated well with the activity of GVHD during clinical course of immunosuppressive treatment. For patients with hepatic GVHD, there is a positive correlation between plasma IL-10 levels and the severity of hepatic injury. The frequency of Th2 is also significant higher in acute GVHD and tends to be higher in chronic GVHD. Interestingly, there is a very good positive correlation between the frequency of Th1 and Th2 (r = 0.951, p<0.001). The plasma level of IL-4 and IL-12 are not associated with the activity of GVHD. Conclusions The frequency of Th1, Th2 within CD4+ T cells and plasma IL-10 and IFN-γ are good biomarkers of GVHD. Plasma IL-10 can also be used to monitor the therapeutic responsiveness. Furthermore, both Th1 and Th2 likely contribute to the pathogenesis of GVHD.

ADAM9 enhances CDCP1 protein expression by suppressing miR-218 for lung tumor metastasis.

Metastasis is the leading cause of death in cancer patients due to the difficulty of controlling this complex process. MicroRNAs (miRNA), endogenous noncoding short RNAs with important biological and pathological functions, may play a regulatory role during cancer metastasis, but this role has yet to be fully defined. We previously demonstrated that ADAM9 enhanced the expression of the pro-migratory protein CDCP1 to promote lung metastasis; however, the regulatory process remains unknown. Here we demonstrate that endogenous miR-218, which is abundant in normal lung tissue but suppressed in lung tumors, is regulated during the process of ADAM9-mediated CDCP1 expression. Suppression of miR-218 was associated with high migration ability in lung cancer cells. Direct interaction between miR-218 and the 3′-UTR of CDCP1 mRNAs was detected in luciferase-based transcription reporter assays. CDCP1 protein levels decreased as expression levels of miR-218 increased, and increased in cells treated with miR-218 antagomirs. Induction of miR-218 inhibited tumor cell mobility, anchorage-free survival, and tumor-initiating cell formation in vitro and delayed tumor metastases in mice. Our findings revealed an integrative tumor suppressor function of miR-218 in lung carcinogenesis and metastasis.

Anti-leukemic therapies induce cytogenetic changes of human bone marrow-derived mesenchymal stem cells

Both bone marrow hematopoietic cells (BM-HCs) and mesenchymal stem cells (BM-MSCs) may have cytogenetic aberrations in leukemic patients, and anti-leukemic therapy may induce cytogenetic remission of BM-HCs. The impact of anti-leukemic therapy on BM-MSCs remains unknown. Cytogenetic studies of BM-MSCs from 15 leukemic patients with documented cytogenetic abnormalities of BM-HCs were investigated. To see the influence of anti-leukemic therapy on BM-MSCs, cytogenetic studies were carried out in seven of them after the completion of anti-leukemic therapy, including anthracycline/Ara-C-based chemotherapy in two patients, high-dose busulfan/cyclophosphamide-based allogeneic transplantation in two patients, and total body irradiation (TBI)-based allogeneic transplantation in three patients. To simulate the effect of TBI in vitro, three BM-MSCs from one leukemic patient and two normal adults were irradiated using the same dosage and dosing schedule of TBI and cytogenetics were re-examined after irradiation. At the diagnosis of leukemia, two BM-MSCs had cytogenetic aberration, which were completely different to their BM-HCs counterpart. After the completion of anti-leukemic therapy, cytogenetic aberration was no longer detectable in one patient. Unexpectedly, BM-MSCs from three patients receiving TBI-based allogeneic transplantation acquired new, clonal cytogenetic abnormalities after transplantation. Similarly, complex cytogenetic abnormalities were found in all the three BM-MSCs exposed to in vitro irradiation. In conclusion, anti-leukemic treatments induce not only “cytogenetic remission” but also new cytogenetic abnormalities of BM-MSCs. TBI especially exerts detrimental effect on the chromosomal integrity of BM-MSCs and highlights the equal importance of investigating long-term adverse effect of anti-leukemic therapy on BM-MSCs as opposed to beneficial effect on BM-HCs.

A targeted next‐generation sequencing in the molecular risk stratification of adult acute myeloid leukemia: implications for clinical practice

Conventional cytogenetics can categorize patients with acute myeloid leukemia (AML) into favorable, intermediate, and unfavorable‐risk groups; however, patients with intermediate‐risk cytogenetics represent the major population with variable outcomes. Because molecular profiling can assist with AML prognosis and next‐generation sequencing allows simultaneous sequencing of many target genes, we analyzed 260 genes in 112 patients with de novo AML who received standard treatment. Multivariate analysis showed that karyotypes and mutation status of TET2, PHF6, KIT, and NPM1mutation/FLT3‐ internal tandem duplication (ITD)negative were independent prognostic factors for the entire cohort. Among patients with intermediate‐risk cytogenetics, patients with mutations in CEBPAdouble mutation, IDH2, and NPM1 in the absence of FLT3‐ITD were associated with improved Overall survival (OS), similar to those with favorable‐risk cytogenetics; patients with mutations in TET2, RUNX1, ASXL1, and DNMT3A were associated with reduced OS, similar to those with unfavorable‐risk cytogenetics. We concluded that integration of cytogenetic and molecular profiling improves prognostic stratification of patients into three groups with more distinct prognoses (P < 0.001) and significantly reduces the number of patients classified as intermediate risk. In addition, our study demonstrates that next‐generation sequencing (NGS)‐based multi‐gene sequencing is clinically applicable in establishing an accurate risk stratification system for guiding therapeutic decisions.

Oxaliplatin-induced long QT syndrome in a patient with appendiceal adenocarcinoma

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[18F]-Fluorodeoxyglucose Positron Emission Tomography Standardized Uptake Value as a Predictor of Adjuvant Chemotherapy Benefits in Patients With Nasopharyngeal Carcinoma

BACKGROUND The role of adjuvant chemotherapy for the treatment of nasopharyngeal carcinoma (NPC) is controversial, and the identification of adequate predictive factors is warranted. Therefore, we aimed to investigate whether the mean standardized uptake value (SUV) measured on [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) could predict the survival benefits for NPC patients that receive adjuvant chemotherapy. MATERIALS AND METHODS The data for 174 NPC patients who underwent PET/computed tomography before chemoradiation between January 2004 and January 2012 were reviewed. The SUV75% was recorded for primary tumors. All patients received intensity-modulated radiotherapy and cisplatin-based chemotherapy. Adjuvant chemotherapy consisted of 3 cycles of 75 mg/m(2) cisplatin and 1,000 mg/m(2) fluorouracil for 4 days. RESULTS The optimal cutoff value was 8.35 for SUV75%, with 112 (64.4%) patients having lower SUV75% and 62 (35.6%) having higher SUV75%. Patients with lower SUV75% had significantly better 5-year overall survival (OS) and distant metastasis-free survival. Multivariate analysis revealed that tumor stage, SUV75%, and adjuvant chemotherapy were significant prognostic factors for OS. Patients with higher SUV75% had significantly higher 5-year OS rates with adjuvant chemotherapy than without adjuvant chemotherapy (84.3% vs. 32.4%, respectively; p < .001). However, in the lower SUV75% group, no differences in 5-year OS were observed between patients who received and those who did not receive adjuvant chemotherapy (92.4% vs. 93.3%, respectively; p = .682). CONCLUSION The SUV75% on FDG PET for primary tumors could successfully identify NPC patients who may benefit from adjuvant chemotherapy.

Perianal tuberculosis during neutropenia: a rare case report and review of literature.

Dear Editor, Neutropenia is the major complication of chemotherapy and definitely increases the risk of infection. Perianal infection could occur during the period of neutropenia, with an incidence of around 7–8% in literature [1]. Of documented infection, almost all the causative pathogens were bacteria, and most of them were caused by hematogenous spreading such as septicemia [2]. Perianal abscess due to tuberculosis infection during neutropenia has never been reported so far. We described the first patient of angioimmunoblastic T-cell lymphoma who developed perianal tuberculosis during neutropenic phase after chemotherapy. A 56-year-old gentleman with stage IVB of angioimmunoblastic T-cell lymphoma, having been treated with chemotherapy (CHOP regimen: cyclophosphamide, doxorubicin, vincrinstine, and prednisolone) eight times and only achieving partial response, was hospitalized for chemotherapy followed by collecting of CD34-positive selected peripheral blood stem cells. During the period of neutropenia, a small painful induration with a size of 0.5×1 cm over perianal area was noted, and fever developed subsequently. Under the impression of perianal abscess, he was treated with metronidazole initially. There was neither pathogens isolated from blood nor evidence of pulmonary infection on chest X-ray. The size of perianal induration progressed to 6×5 cm, and the involved skin became erythematous. Surgical debridement was thus performed, and tuberculosis infection was surprisingly identified by the pathologist (Fig. 1). After surgical debridement and anti-TB chemotherapy, the wound improved and he became afebrile. Neutropenia is common in patients of various hematological diseases, especially after intensive chemotherapy or hematopoietic stem cell transplantation. Infection is the major cause of morbidity and mortality in these patients, even using granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) to provide increasing neutrophil counts [3]. Among the microorganisms of infection, bacteria are most common and relatively easier to be recognized, as in the case of perianal abscess. However, perianal abscess due to tuberculosis infection during the period of neutropenia has never been reported so far. Tuberculosis infection can be divided into three categories: pulmonary, extrapulmonary alone, or both. There are some difficulties of identifying perianal tuberculosis. First, the incidence of the perianal infection itself is relatively lower, and the common causative agent is bacteria. Second, there are no significant characteristics of symptoms and signs at the infectious site to differentiate the causative organisms initially. Most symptoms in perianal tuberculosis mimic those in other common pathogen infections. It is usually diagnosed by biopsy after the prolonged course of ulceration or poor response to empiric antibiotic therapy [4]. We may ignore this condition owing to less experience, especially if no coexisting pulmonary infection was identified. So, if tuberculosis was suspected, histopathologic confirmation from perianal abscess must be made [5]. Treatment of perianal tuberculosis is the standard regimen, including three or four combined agents. Surgical intervention should be considered when there is obstruction or frank abscess [4]. In summary, perianal tuberculosis can be the etiology of febrile neutropenia. It is difficultly diagnosed because perianal biopsy is the only way to make the accurate diagnosis, and thus, effective treatment can be performed. C.-Y. Lin . S.-P. Yeh . H.-H. Huang . Y.-M. Liao . C.-F. Chiu (*) Department of Internal Medicine, Division of Haematology and Oncology, China Medical University Hospital, 2 Yu-Der Road, Taichung, 404, Taiwan e-mail: jnynlin@gmail.com Tel.: +886-4-22052121 Fax: +886-4-22034421