Young Saing Kim

Epidermal Growth Factor Receptor Mutations and the Clinical Outcome in Male Smokers with Squamous Cell Carcinoma of Lung

Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) have been reported to be related to certain clinical characteristics (i.e., female, non-smokers with adenocarcinoma) and gefitinib responsiveness. This exploratory analysis was performed to determine the incidence of EGFR mutations in male smokers with squamous cell carcinoma, who were treated with EGFR tyrosine kinase inhibitor, gefitinib. Sixty-nine Korean NSCLC patients were treated with gefitinib in a prospective study. For a subset of 20 male patients with squamous cell carcinoma and a history of smoking, pretreatment tumor tissue samples were obtained and analyzed for EGFR mutations (exons 18 to 21). EGFR mutations were found in 3 (15%) patients, including in-frame deletions within exon 19 (n=2) and L858R missence mutation in exon 21 (n=1). These 3 patients with EGFR mutations responded to gefitinib, whereas only one of remaining 17 patients with wild-type EGFR achieved clinical response. Trend toward longer progression-free (5.8 vs. 2.4 months; P=0.07) was noted in patients with EGFR mutations compared to those with wild-type EGFR. Although male smokers with squamous cell carcinoma have not been considered ideal candidates for gefitinib treatment, significant incidence of EGFR mutations was observed. The molecular markers should be considered to predict clinical benefits from gefitinib.

Prognostic Significance of CT-Determined Sarcopenia in Patients with Small-Cell Lung Cancer

Introduction: The primary objective of this study was to determine the prognostic significance of computed tomography (CT)-determined sarcopenia in small-cell lung cancer (SCLC) patients. Methods: This retrospective study consisted of a total of 149 consecutive SCLC patients. The cross-sectional area of muscle at the level of the third lumbar vertebra (L3) was measured using baseline CT images. Sarcopenia was defined as a L3 muscle index of less than 55 cm2/m2 for men and of less than 39 cm2/m2 for women as proposed by international consensus of cancer cachexia. In addition, Korean-specific cutoffs for sarcopenia was also applied (49 cm2/m2 for men and 31 cm2/m2 for women). Overall survival (OS) and clinical characteristics of patients with or without sarcopenia were compared. Results: Mean patient age was 68.6 ± 9.5 years. Most were male (85.3%) and 67.8% had extensive disease at time of diagnosis. Sarcopenia was present in 118 patients (79.2%) and was significantly related to an advanced age (p = 0.028), male sex (p < 0.001), lower body mass index (p < 0.001), and poor performance status (p = 0.049). Sarcopenic patients had shorter OS than nonsarcopenic patients (median: 8.6 months versus 16.8 months; p = 0.031). Multivariable analysis revealed that sarcopenia was an independent prognostic factor of poor survival (hazards ratio: 1.68; 95% confidence interval: 1.04–2.72; p = 0.034), along with extensive stage (p < 0.001), supportive care only (p < 0.001), and an elevated lactate dehydrogenase level (p = 0.020). Using Korean sarcopenia cutoffs, sarcopenic patients were also found to have poorer OS than nonsarcopenic patients, however, the survival difference was not statistically significant (median: 8.4 months versus 12.7 months; p = 0.144 by the log-rank test). Conclusions: Sarcopenia as determined by CT could be used to predict prognosis in patients with SCLC. Optimum reference values to predict cancer-specific outcomes should be tailored by further studies.

Oxaliplatin, 5-fluorouracil and Leucovorin (FOLFOX-4) Combination Chemotherapy as a Salvage Treatment in Advanced Gastric Cancer

PURPOSE This study was designed to determine the efficacy and safety of FOLFOX-4 chemotherapy as a salvage treatment for patients with advanced gastric cancer (AGC). MATERIALS AND METHODS The AGC patients with an ECOG performance status of 0~1 and progressive disease after prior treatments were registered onto this phase II trial. The patients received oxaliplatin (85 mg/m² on day 1), leucovorin (200 mg/m² on days 1 and 2) and 5-fluorouracil (400 mg/m² as a bolus and 600 mg/m² as a 22-hour infusion on days 1 and 2) every 2 weeks. RESULTS For the 42 treated patients, a total of 228 chemotherapy cycles (median: 5, range: 1~12) were administered. Twenty-nine patients (69%) received FOLFOX-4 chemotherapy as a third-(50%) or fourth-line (19%) treatment. On the intent-to-treat analysis, 9 patients (21%) achieved a partial response, which was maintained for 4.6 months. The median progression-free survival and overall survival were 3.0 months and 6.2 months, respectively. The frequently encountered toxicities were neutropenia and gastrointestinal side effects, including anorexia. Although there was one possible treatment-related death, the toxicity profiles were generally predictable and manageable. CONCLUSION Salvage chemotherapy with FOLFOX-4 is an effective and tolerable regimen for those heavily pretreated AGC patients who have a good performance status.

Effect of paclitaxel/carboplatin salvage chemotherapy in noncutaneous versus cutaneous metastatic melanoma.

Little is known about the efficacy of salvage chemotherapy for patients with metastatic, noncutaneous melanoma after the failure of dacarbazine-based chemotherapy. Because of the high incidence of noncutaneous melanoma in Korea, we assessed the outcomes of paclitaxel/carboplatin (PC) salvage chemotherapy in patients with noncutaneous metastatic melanoma. We retrospectively analyzed patients with metastatic melanoma who received intravenous paclitaxel (175 mg/m2) plus intravenous carboplatin (area under the curve 5) on day 1 of a 21-day cycle as salvage chemotherapy at Samsung Medical Center (SMC) between February 2009 and February 2012. The overall response rate, overall survival, and progression-free survival were evaluated. Thirty-two patients with a median age of 54 years (range 24–72 years) received PC as salvage chemotherapy. All patients had been pretreated with a median of three systemic chemotherapies. Of the 32 patients, 10 (31.3%) had cutaneous melanoma, eight (25%) had acral melanoma, 10 (31.3%) had mucosal melanoma, and two (6.3%) had ocular melanoma. In response to treatment, seven of the 32 patients (21.9%) achieved partial response and 11 (34.4%) had stable disease. The median progression-free survival was 2.53 months for all patients, 4.3 months for patients with controlled disease (partial response and stable disease), and 1.37 months for patients with progressive disease (P=0.0001). The median overall survival was 5.2 months. No significant difference was noted between patients with noncutaneous and cutaneous metastatic melanoma (P=0.75). PC salvage chemotherapy may be a reasonable therapeutic option for heavily pretreated metastatic melanoma patients. Salvage therapy with this combination had definite clinically meaningful benefits in patients with metastatic melanoma, including those with noncutaneous melanoma.

Positive Correlation between Baseline PET or PET/CT Findings and Clinical Parameters in Multiple Myeloma Patients

Recently, positron emission tomography (PET) has been incorporated into a series of prospective studies as a predictor of outcomes in multiple myeloma (MM), and the number of 18F-fluorodeoxuglucose (FDG)-avid focal lesions (FLs) and the intensity of tumor metabolism have been designated as important surrogate markers for predicting prognosis. Here, we compared initial clinical characteristics of MM patients with baseline PET parameters: the number of FLs and the maximum standardized uptake value (SUVmax). A total of 59 patients diagnosed with MM between August 2004 and February 2012 were reviewed. At diagnosis, 23 patients (40.0%) had ≤3 FLs, 11 patients (18.6%) 4-9 FLs, and 25 patients (42.4%) ≥10 FLs. The median SUVmax was 5.3 (range 0-24.3), and 40 patients (67.8%) showed a SUVmax >4. No clinical characteristics were significantly different between groups with a SUVmax ≤4 and a SUVmax >4. However, there were significant differences in several clinical indices between the FLs ≤3 and FLs >3 groups; elevated β2-microglobulin, elevated lactate dehydrogenase, anemia and more advanced disease by the Durie-Salmon stage corresponded to FLs >3 at baseline PET. Adverse baseline PET findings are positively correlated with prognostically relevant clinical parameters. Regarding PET parameters, FLs are more likely to be well correlated with disease aggressiveness and pathophysiology compared to SUVmax.

Epidermal growth factor receptor (EGFR) exon 20 mutations in non-small-cell lung cancer and resistance to EGFR-tyrosine kinase inhibitors

SummaryIntroduction In patients with non-small cell lung cancer (NSCLC), the predictive value of rare epidermal growth factor receptor (EGFR) exon 20 mutations in determining a patient’s response to EGFR tyrosine kinase inhibitor (TKI) treatment is unclear. Patients and Methods We reviewed data for NSCLC patients harboring EGFR exon 20 mutations from two hospitals in Korea. EGFR mutations were analyzed using directional sequencing. Results We identified eight patients carrying EGFR exon 20 mutations, seven of whom had insertional mutations. Three patients carried previously unreported insertional mutations. Among six patients who were treated with EGFR TKI, one showed stable disease and three showed primary resistance. Response evaluations were not performed for the other two patients because of their clinical deterioration. Conclusions EGFR exon 20 insertional mutations, including three that were previously unreported, were associated with the poor response of patients to TKI treatment.

The impact of activated p-AKT expression on clinical outcomes in diffuse large B-cell lymphoma: a clinicopathological study of 262 cases

BACKGROUND Oncogenic phosphatidylinositol-3-kinase/serine-threonine kinase (PI3K/AKT) pathway plays a critical role in cell proliferation and growth. Phosphorylated AKT (p-AKT) has been reported to be abnormally overexpressed and to have poor prognostic impact in solid tumors. PATIENTS AND METHODS To define the clinical implications of p-AKT expression in diffuse large B-cell lymphoma (DLBCL), we calculated arbitrary units (AUs) by multiplying the intensity and the proportion of p-AKT expression and investigated the impact of p-AKT expression on clinical outcomes. We assessed 262 patients with DLBCL. Based on a cutoff value of the upper limit of the third quartile of AUs, 56 patients were classified as high p-AKT and the remaining 206 patients were classified as low p-AKT. RESULTS The high p-AKT group was closely associated with more advanced stage (stage III-IV, P = 0.02), two or more extranodal involvement (P = 0.03), lactic dehydrogenase elevation (P = 0.03), higher International Prognostic Index risk groups (high intermediate/high, P = 0.02), and the presence of B-symptoms (P = 0.01). The high p-AKT group showed substantially worse overall survival (OS) (median OS, 115.0 months versus not reached, P = 0.004) and progression-free survival (PFS) (median PFS, 25.5 versus 105.8 months, P = 0.019) compared with the low p-AKT group. Multivariate analysis revealed that high p-AKT expression retained its significant poor prognostic impact for OS (hazard ratio 1.7; 95% confidence interval, 1.0-2.7; P = 0.031). The subgroup with high p-AKT expression and concurrent Epstein-Barr virus positivity showed worst prognosis with the median OS and PFS of 15.2 and 7.4 months. CONCLUSION DLBCL patients with high p-AKT expression showed distinct clinical features and followed a more rapidly deteriorating clinical course with worse OS and PFS. Thus, a more effective treatment option should be developed for this subset of DLBCL patients, and targeting PI3K/AKT pathway may be a promising therapeutic strategy.

Epidermal growth factor receptor mutation and pattern of brain metastasis in patients with non-small cell lung cancer.

Background/Aims We investigated the time taken for patients with metastatic non-small cell lung cancer (NSCLC) to develop brain metastases (BM), as well as their subsequent overall median survival following diagnosis, considering the epidermal growth factor receptor (EGFR) mutational status. Methods We retrospectively investigated the medical records of 259 patients diagnosed with advanced NSCLC from January 2010 to August 2013, who were tested for EGFR mutations. The time from the diagnosis of advanced NSCLC to the development of BM and the overall median survival after BM development (BM-OS) were evaluated and compared by EGFR mutational status. Results Sixty-seven patients (25.9%) developed BM. Synchronous BM occurred more often in patients with EGFR mutation type (MT) (n = 20, 27.4%) compared with EGFR wild type (WT) (n = 27, 14.5%, p < 0.009). The median BM-OS was significantly longer in patients with EGFR MT than in those with EGFR WT (25.7 months vs. 3.8 months, p < 0.001), and a similar trend was noticed for patients with synchronous BM (25.7 months for EGFR MT vs. 6.8 months for EGFR WT, p < 0.001). However, in patients with metachronous BM development, the difference in BM-OS between patients with EGFR MT (14.6 months) and EGFR WT (2.5 months) did not reach statistical significance (p = 0.230). Conclusions Synchronous BM was more common in NSCLC patients with EGFR MT than in those with EGFR WT. However, EGFR mutations were associated with significantly longer median BM-OS, especially when the brain was the first metastatic site.

The Relationship between Sarcopenia and Systemic Inflammatory Response for Cancer Cachexia in Small Cell Lung Cancer.

Background The prognostic significance of sarcopenia, an important component of cancer cachexia, has been demonstrated in oncologic patients. Catabolic drivers have been suggested to be key features of cancer cachexia. Objective To determine the relationship between systemic inflammatory markers and CT-determined muscle mass in patients with SCLC. Methods Cross-sectional muscle areas were evaluated at the level of the third lumbar vertebra (L3) using baseline CT images in 186 SCLC patients. Sarcopenia was defined as a L3 muscle index (L3MI, muscle area at L3/height2) of < 55 cm2/m2 for men and of < 39 cm2/m2 for women. Systemic inflammatory markers investigated included serum white blood cell count (WBC), neutrophil: lymphocyte ratio (NLR), C-reactive protein (CRP), and albumin. Results Mean L3MI was 47.9 ± 9.7 cm2/m2 for men and 41.6 ± 7.0 cm2/m2 for women. Sarcopenia was present in 128 patients (68.8%), and sarcopenic patients had significant serum lymphocyte counts and albumin levels (p = 0.002 and 0.041, respectively), and higher NLRs and CRP levels (p = 0.011 and 0.026) than non-sarcopenic patients. Multivariable analysis revealed that CRP independently predicted L3MI (β = -0.208; 95% CI, -0.415 to -0.002; p = 0.048), along with gender and BMI (p values < 0.001) and performance status (p = 0.010). Conclusion The present study confirms a significant linear relationship exists between CT-determined muscle mass and CRP in SCLC patients. This association might provide a better understanding of the mechanism of cancer cachexia.

Matched-Pair Analysis Comparing the Outcomes of T Cell/Histiocyte-Rich Large B Cell Lymphoma and Diffuse Large B Cell Lymphoma in Patients Treated with Rituximab-CHOP

Background: T cell/histiocyte-rich large B cell lymphoma (THRLBCL) is a rare morphological variant of diffuse large B cell lymphoma (DLBCL), accounting for 1-3% of all DLBCLs. However, its impact on treatment outcome and prognosis is still not clearly defined. Methods: We compared the clinical outcomes between THRLBCL and DLBCL, not otherwise specified (NOS), in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Results: Data from 11 patients with THRLBCL were matched to 33 patients with DLBCL-NOS. Patients were matched by five established prognostic factors of the International Prognostic Index, including age, Ann Arbor stage, Eastern Cooperative Oncology Group performance status, serum lactate dehydrogenase level and the number of extranodal involvement. There was no significant difference in the complete response rate to R-CHOP between THRLBCL (91%, 10/11) and DLBCL-NOS (97%, 32/33; p = 0.442). The 3-year event-free survival rate was 81% for both THRLBCL and DLBCL-NOS (p = 0.813). The 3-year overall survival rates were 75 and 81%, respectively (p = 0.719). Conclusions: The treatment outcomes of THRLBCL are similar to those of DLBCL-NOS. The addition of rituximab to CHOP seems to be helpful for the management of THRLBCL, as it is for DLBCL-NOS.