Jeong-Ok Lee

Anaplastic lymphoma kinase translocation: a predictive biomarker of pemetrexed in patients with non-small cell lung cancer.

Introduction: This study compared the efficacy of pemetrexed in patients with anaplastic lymphoma kinase (ALK)-positive versus ALK-negative (epidermal growth factor receptor [EGFR] mutant or wild type [WT] for both ALK and EGFR) non-small cell lung cancer (NSCLC). Methods: Patients with advanced NSCLC who received second-line pemetrexed and beyond between March 2007 and April 2010 were screened for EGFR mutations and ALK rearrangements at Seoul National University Hospital. The clinical and in vitro efficacy of pemetrexed was evaluated for each genotypic group. Results: Ninety-five NSCLC patients were genotyped as follows: 43 (45%) EGFR mutation, 15 (16%) ALK translocation, and 37 (39%) WT. The overall response rate was superior in ALK-translocated patients compared with EGFR mutant or WT patients (46.7 versus 4.7 versus 16.2%, p = 0.001). ALK-positive patients showed longer time to progression than EGFR mutant or WT patients (9.2 versus 1.4 versus 2.9 months, p = 0.001). ALK positivity alone was a significant predictor for overall response rate (hazard ratio [HR] = 0.07, 95% confidence interval [CI]: 0.01–0.32; p = 0.001) and time to progression (HR = 0.44, 95% CI: 0.24–0.80; p = 0.007). ALK positivity remained independently significant regardless of treatment line (HR = 0.43, 95% CI: 0.24–0.77; p = 0.005). Thymidylate synthase mRNA levels in ALK-positive cells were significantly lower compared with control cells (p < 0.05). Conclusion: Pemetrexed is an effective treatment in patients with ALK-positive NSCLC. ALK positivity was independently predictive of pemetrexed efficacy in NSCLC patients.

Different metastatic pattern according to the KRAS mutational status and site-specific discordance of KRAS status in patients with colorectal cancer

BackgroundWe evaluated the association between a KRAS mutational status and various clinicopathologic features including the metastatic pattern in patients with metastatic or recurrent colorectal cancer (MRCRC). The concordance rates of the KRAS status between primary tumor sites and paired metastatic organs were also analyzed.MethodsThe KRAS mutational status in codons 12, 13, and 61 from formalin-fixed sections of both primary tumors and related metastases was determined by sequencing analysis. One hundred forty-three Korean patients with MRCRC with available tissues (resection or biopsy) from both primary tumors and related metastatic sites were consecutively enrolled.ResultsThe KRAS mutation rate was 52.4% (75/143) when considering both the primary and metastatic sites. When the relationship between the KRAS status and initial metastatic sites at the time of diagnosis of MRCRC was analyzed, lung metastasis was more frequent as the initial metastatic site in patients with the KRAS mutation than in patients without the KRAS mutation (45.3% vs. 22.1%; P = 0.003). However, liver (37.3% vs. 70.6%; P < 0.001) or distant lymph node metastases (6.7% vs. 19.1%; P = 0.025) were less frequent as the initial metastatic organ in patients with the KRAS mutation than in patients without the KRAS mutation. The discordance rate of KRAS mutational status between primary and paired metastatic sites other than the lung was 12.3% (13/106). Compared with primary tumor sites, the KRAS discordance rate was significantly higher in matched lung metastases [32.4% (12/37)] than in other matched metastatic organs (P = 0.005).ConclusionsOrgans initially involved by distant metastasis were different according to the KRAS mutational status in MRCRC patients. The concordance rate (87.7%) of the KRAS mutation status at metastatic sites other than the lung was generally high compared with primary tumor sites; however, lung metastasis had a high rate of KRAS discordance (32.4%).

Clinical outcomes of leptomeningeal metastasis in patients with non-small cell lung cancer in the modern chemotherapy era

BACKGROUND We analyzed the patterns of treatment and clinical outcomes of leptomeningeal metastasis (LM) in patients with non-small cell lung cancer (NSCLC) in the modern chemotherapy era. METHODS We retrospectively reviewed the data of NSCLC patients who were diagnosed with LM between 2003 and 2009 at Seoul National University Bundang Hospital. RESULTS Of the 50 patients with cytologically proven LM, 25 were male (50%), 14 (28%) had an ECOG performance status (PS) ≥ 3, and the median age was 62.5 years (range, 34-81 years). The patients were diagnosed with LM after a median of 10.4 months (range, 0-86.8 months) from the initial diagnosis of metastatic NSCLC. LM was present in 11 patients at the time of initial diagnosis. The median overall survival (OS) after the diagnosis of LM was 4.3 months (95% CI, 1.5-6.7 months). Forty-eight patients (96%) received intrathecal chemotherapy and the cytological response rate was 52%. The median survival was 5.5 months in cytological responders and 1.4 months in non-responders (p=0.075). The median OS in patients with an ECOG PS of 1-2 was longer than patients with an ECOG PS of 3-4 (5.5 vs. 0.7 months, p<0.001). Twenty-two patients (44%) received systemic cytotoxic chemotherapy or an EGFR tyrosine kinase inhibitor (TKI) after being diagnosed with LM. These patients had prolonged survival (11.5 vs. 1.4 months, p<0.001), and in 14 patients (28%) who received an EGFR TKI, the median OS was 19.2 months. In subgroup of patients with an ECOG PS of 1-2, those who received further systemic chemotherapy had improved survival compared to patients who did not receive further chemotherapy (11.5 vs. 2.1 months, p<0.001). CONCLUSION NSCLC patients with LM exhibited diverse clinical outcomes rather than a uniformly poor prognosis. Systemic chemotherapy, especially EGFR TKIs in addition to intrathecal chemotherapy, might confer a survival benefit.

CD15+/CD16low human granulocytes from terminal cancer patients: granulocytic myeloid-derived suppressor cells that have suppressive function

Myeloid-derived suppressor cells (MDSCs) are a subpopulation of myeloid cells with immunosuppressive function whose numbers are increased in conditions such as chronic infection, trauma, and cancer. Unlike murine MDSCs defined as CD11b+/Gr-1+, there are no specific markers for human MDSCs. The goal of this study was to delineate a specific human MDSCs subpopulation in granulocytes from terminal cancer patients and investigate its clinical implications. Here, we show that the CD15+/CD16low subset was increased in terminal cancer patients compared with healthy donors (P = 0.009). Phorbol 12-myristate 13-acetate-activated granulocytes (CD16low/CD66b++/CD15+) that have a phenotype similar to MDSCs from cancer patients, effectively suppressed both proliferation and cytotoxicity of normal T cells. Among cancer patients, T-cell proliferation was highly suppressed by granulocytes isolated from terminal cancer patients with a high proportion of CD15+/CD16low cells. Patients with low peripheral blood levels of CD15+/CD16low cells had significantly longer survival than those with high levels (P = 0.0011). Patients with higher levels of CD15+/CD16low also tended to have poor performance status (P = 0.05). These data suggest that CD15+/CD16low granulocytes found in terminal cancer patients may play a role in the progression of cancer by inhibiting tumor immunity.

Prognostic value of metabolic tumor volume on PET / CT in primary gastrointestinal diffuse large B cell lymphoma

Primary gastrointestinal (PGI) diffuse large B cell lymphoma (DLBCL) is a relatively common disease. Recent studies indicate that measurement of maximum standardized uptake value (SUVmax) on pretreatment for 18F‐fluorodeoxyglucose PET is an important prognostic factor in PGI DLBCL. However, there is still an association between initial tumor burden and prognosis. Thus, in the present study, we investigated whether tumor volume by PET could have a potential prognostic value to predict the outcome. From 2006 to 2009, 165 Stage I E/II E PGI DLBCL patients were enrolled in the study. One hundred and five patients received cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R‐CHOP) only, whereas 60 patients underwent surgery plus R‐CHOP. Metabolic tumor volume (MTV) was defined initial tumor burden as target GI lesion above SUV, 2.5 by PET as a contouring border. Over a median follow‐up period of 36.6 months, receiver operating characteristic (ROC) analysis indicated that the best cut‐off values for MTV and SUVmax were 160.1 cm3 and 12.0, respectively. The estimated area under the ROC curve was higher for MTV than SUVmax. Thus, MTV was a better predictor for survival than SUVmax. In patients with a low MTV (<160.1 cm3), there were no significant differences in survival between patients undergoing R‐CHOP alone and surgery plus R‐CHOP (P = 0.347 for progression‐free survival [PFS]; P = 0.148 for overall survival [OS]). Conversely, in patients with a high MTV (>160.1 cm3), survival was longer in those who underwent surgery plus R‐CHOP than in those treated with R‐CHOP alone (P < 0.001 for PFS; P < 0.001 for OS). Multivariate analysis revealed that high MTV is an independent factor for predicting survival. Even in the era of rituximab, treatment of PGI DLBCL is not easy in patients with a high MTV. (Cancer Sci 2012; 103: 477–482)

Palliative chemotherapy for patients with recurrent hepatocellular carcinoma after liver transplantation

Background and Aim:  The majority of patients with post‐transplantation recurrence of hepatocellular carcinoma (HCC) have extrahepatic metastases and multifocal lesions. Therefore, they have few treatment options and may not be amenable for local therapy. The safety and efficacy of palliative chemotherapy in this population has not been reported.

Metastatic Adrenocortical Carcinoma Treated with Sunitinib: A Case Report

Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. Palliative chemotherapy can be considered in patients with metastatic disease. Although mitotane- or cisplatin-based chemotherapy regimens are widely used, the effects of these agents have been limited. We have experienced a case that showed a partial response with sunitinib after failure of mitotane-based cytotoxic chemotherapy. The clinical benefit from sunitinib persisted 7.5 months in this case. To our knowledge, this is the first reported case showing the effects of sunitinib on metastatic ACC.

p21-Activated Kinase 4 (PAK4) as a Predictive Marker of Gemcitabine Sensitivity in Pancreatic Cancer Cell Lines.

Purpose p21-activated kinases (PAKs) are involved in cytoskeletal reorganization, gene transcription, cell proliferation and survival, and oncogenic transformation. Therefore, we hypothesized that PAK expression levels could predict the sensitivity of pancreatic cancer cells to gemcitabine treatment, and PAKs could be therapeutic targets. Materials and Methods Cell viability inhibition by gemcitabine was evaluated in human pancreatic cancer cell lines (Capan-1, Capan-2, MIA PaCa-2, PANC-1, Aspc-1, SNU-213, and SNU-410). Protein expression and mRNA of molecules was detected by immunoblot analysis and reverse transcription polymerase chain reaction. To define the function of PAK4, PAK4 was controlled using PAK4 siRNA. Results Capan-2, PANC-1, and SNU-410 cells were resistant to gemcitabine treatment. Immunoblot analysis of signaling molecules reported to indicate gemcitabine sensitivity showed higher expression of PAK4 and lower expression of human equilibrative nucleoside transporter 1 (hENT1), a well-known predictive marker for gemcitabine activity, in the resistant cell lines. Knockdown of PAK4 using siRNA induced the upregulation of hENT1. In resistant cell lines (Capan-2, PANC-1, and SNU-410), knockdown of PAK4 by siRNA resulted in restoration of sensitivity to gemcitabine. Conclusion PAK4 could be a predictive marker of gemcitabine sensitivity and a potential therapeutic target to increase gemcitabine sensitivity in pancreatic cancer.

Effectiveness of increasing the frequency of posaconazole syrup administration to achieve optimal plasma concentrations in patients with haematological malignancy

Few data are available on whether adjusting the dose of posaconazole syrup is effective in patients receiving anti-cancer chemotherapy. The aim of this prospective study was to analyse the impact of increasing the frequency of posaconazole administration on optimal plasma concentrations in adult patients with haematological malignancy. A total of 133 adult patients receiving chemotherapy for acute myeloid leukaemia or myelodysplastic syndrome who received posaconazole syrup 200 mg three times daily for fungal prophylaxis were enrolled in this study. Drug trough levels were measured by liquid chromatography-tandem mass spectrometry. In 20.2% of patients (23/114) the steady-state concentration of posaconazole was suboptimal (<500 ng/mL) on Day 8. In these patients, the frequency of posaconazole administration was increased to 200 mg four times daily. On Day 15, the median posaconazole concentration was significantly increased from 368 ng/mL [interquartile range (IQR), 247-403 ng/mL] to 548 ng/mL (IQR, 424-887 ng/mL) (P = 0.0003). The median increase in posaconazole concentration was 251 ng/mL (IQR, 93-517 ng/mL). Among the patients with initially suboptimal levels, 79% achieved the optimal level unless the steady-state level was <200 ng/mL. This study shows that increasing the administration frequency of posaconazole syrup is effective for achieving optimal levels in patients with haematological malignancy undergoing chemotherapy.

Gastric cancer with initial bone metastasis: A distinct group of diseases with poor prognosis

BACKGROUND Bone metastasis (BM) is reported as a poor prognostic factor in gastric cancer. However, the clinicopathologic characteristics and clinical outcomes of patients with BM compared with patients without BM have not been well described. PATIENTS AND METHODS The medical records of all metastatic or recurrent gastric cancer (MRGC) patients who visited our institution were reviewed. A total of 137 evaluable patients with BM were analysed together with historical control without BM (N=111). RESULTS Of 1342 MRGC patients, 141 (10.5%) had BM. Patients with BM could be divided into initial BM (BM present at initial diagnosis of MRGC; N=90) and late BM (N=47) groups. The median survival after the diagnosis of BM in all patients was 4.4 months (95% confidence interval [CI] 3.69-5.11). However, overall survival after the diagnosis of MRGC was significantly shorter in the initial BM group (5.0 versus 12.2 months, p<0.001). Compared with historical controls, patients with initial BM showed distinct clinicopathologic characteristics. Independent predictors of initial BM were a younger age, signet ring cell histology, primary tumour involving ⩾two-thirds of the stomach, pleural metastasis, thrombocytopenia and elevated alkaline phosphatase. According to a Cox proportional hazard model including both patients with BM and historical controls, initial BM, poor performance status, peritoneal metastasis, hypercalcemia and high carcinoembryonic antigen (CEA) were identified as poor prognostic factors, whereas chemotherapy was identified as a favourable factor (hazard ratio [HR] 0.33, 95% CI 0.22-0.49). CONCLUSION MRGC with initial BM is a distinct group of diseases with specific clinicopathologic characteristics and poor prognosis. Chemotherapy may improve survival in these patients.