Heung Tae Kim

Fibroblasts from chronic wounds show altered TGF-β-signaling and decreased TGF-β Type II Receptor expression†

Chronic wounds are characterized by failure to heal in a defined time frame. However, the pathogenic steps leading from the etiological factors to failure to heal are unknown. Recently, increasing evidence suggests that resident cells in chronic wounds display a number of critical abnormalities, including senescence and unresponsiveness to the stimulatory action of transforming growth factor‐β1 (TGF‐β1). In this study, we have determined some of the mechanisms that might be responsible for unresponsiveness to TGF‐β1. Using Northern analysis and affinity labeling, we show that venous ulcer fibroblasts have decreased TGF‐β Type II receptor expression. This finding is not the result of genetic mutation, as shown by experiments with Type II receptor satellite instability. Decreased Type II receptor expression was accompanied by failure of ulcer fibroblasts to phosphorylate Smad 2, Smad 3, and p42/44 mitogen activating protein kinase (MAPK), and was associated with a slower proliferative rate in response to TGF‐β1. We conclude that venous ulcer fibroblasts show decreased Type II receptor expression and display abnormalities in the downstream signaling pathway involving MAPK and the early Smad pathway. These findings suggest ways to address and treat the abnormal cellular phenotype of cells in chronic wounds.

A randomized phase II study of gefitinib plus simvastatin versus gefitinib alone in previously treated patients with advanced non-small cell lung cancer.

Purpose: To evaluate the efficacy and safety of gefitinib plus simvastatin (GS) versus gefitinib alone (G) in previously treated patients with advanced non–small cell lung cancer (NSCLC). Experimental Design: Between May 2006 and September 2008, 106 patients (51% men, 75% adenocarcinoma, 50% never smoker) were randomly assigned to G alone (250 mg/d, n = 54) or GS (250 and 40 mg/d, respectively, n = 52). One cycle was 4 weeks of treatment. Therapy was continued until disease progression or intolerable toxicity was observed. The primary endpoint was response rate (RR). Secondary endpoints included toxicity, progression-free survival (PFS), and overall survival (OS). Results: The RR was 38.5% (95% CI, 25.3–51.7) for GS and 31.5% (95% CI, 19.1–43.9) for G. The median PFS was 3.3 months [M] (95% CI, 1.4–5.2M) for GS and 1.9M (95% CI, 1.0–2.8M) for G. The median OS was 13.6M (95% CI, 7.1–20.1M) for GS and 12.0M (95% CI, 7.8–16.2M) for G. In exploratory subgroup analysis, GS showed higher RR (40% vs. 0%, P = 0.043) and longer PFS (3.6M vs. 1.7M, P = 0.027) compared with G alone in patients with wild-type epidermal growth factor receptor (EGFR) nonadenocarcinomas. Adverse events in both arms were generally mild and mainly consisted of skin rashes. Conclusions: Although no superiority of GS to G was demonstrated in this unselected NSCLC population, GS showed higher RR and longer PFS compared with G alone in patients with wild-type EGFR nonadenocarcinomas. Simvastatin may improve the efficacy of gefitinib in that subgroup of gefitinib-resistant NSCLC patients. Clin Cancer Res; 17(6); 1553–60. ©2011 AACR.

Comparison of clinical outcome of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations

Aims Deletion of exon 19 of the epidermal growth factor receptor (EGFR) and mutation of exon 21 are the most common EGFR mutations and predict higher response to EGFR tyrosine kinase inhibitors (TKI). Accumulating data show clinical differences in both response and survival between these two EGFR mutations. This study investigated the clinical impact of EGFR exon 19 deletion and L858R mutation by retrospectively analysing the clinical outcome of patients with advanced non-small-cell lung cancer (NSCLC) treated with EGFR TKI. Methods Patients harbouring EGFR exon 19 deletion or L858R mutations and who had received gefitinib or erlotinib treatment were identified. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were determined for the two groups. EGFR mutation was determined by PCR-based direct sequencing. Results The study indentified 87 patients harbouring EGFR exon 19 deletion (n=61) or L858R mutation (n=26) who were treated with either gefitinib (n=83) or erlotinib (n=4). Patients with exon 19 deletion had significantly longer PFS, compared with patients with L858R mutation (9.3 vs 6.9u2005months, p=0.02). In a multivariate Cox regression model, EGFR exon 19 deletion was independently predictive of longer PFS (p=0.02). However, no significant differences in RR (64% vs 62%, p=0.83) and OS (17.7 vs 20.5u2005months, p=0.65) were observed between these two mutations. Conclusions While no significant difference in OS was observed between EGFR exon 19 deletion and L858R mutation, EGFR exon 19 deletion was predictive of longer PFS following EGFR TKI treatment in patients with advanced NSCLC.

Early neutrophil-to-lymphocyte ratio reduction as a surrogate marker of prognosis in never smokers with advanced lung adenocarcinoma receiving gefitinib or standard chemotherapy as first-line therapy.

PurposeAn inflammatory–immunological marker, neutrophil-to-lymphocyte ratio (NLR), was evaluated as a surrogate indicator for prognosis of advanced lung adenocarcinoma patients.MethodsThe subjects of this study were 199 never smokers with advanced lung adenocarcinoma, who were enrolled in a prospective randomized phase III study (First-SIGNAL) comparing gefitinib with gemcitabine plus cisplatin as first-line therapy. The values of NLR were assessed at two time points: at baseline (pretreatment) and on day 1 of the second cycle (posttreatment).ResultsA higher posttreatment NLR was associated with a worse tumor response (median posttreatment NLR, 1.56 for partial response, 1.64 for stable disease, and 2.70 for progressive disease; Pxa0<xa00.001). The risk of progression was higher when the posttreatment NLR was higher [hazard ratio (HR)xa0=xa01.23, 95xa0% confidence interval (CI) 1.15–1.31; Pxa0<xa00.001]. A high posttreatment NLR was associated with an increased risk of death (HRxa0=xa01.13, 95xa0% CI 1.06–1.21; Pxa0<xa00.001). These associations did not differ according to treatment arms. When total patients were divided into four groups according to the cutoff points of pre- and posttreatment NLRs, those with a high pretreatment NLR that declined substantially after treatment showed improved survival compared with those with a high pretreatment NLR that remained high even after treatment (median overall survival, 22.0 and 15.8xa0months, respectively; Pxa0<xa00.001).ConclusionsA high posttreatment NLR is associated with poor prognosis. An early reduction in the NLR after effective treatment may indicate survival improvement in the patients with poor prognosis.

Circulating Cell-Free DNA in Plasma of Never Smokers with Advanced Lung Adenocarcinoma Receiving Gefitinib or Standard Chemotherapy as First-Line Therapy

Purpose: Circulating cell-free DNA (CFDNA) was investigated as potential screening or prognostic markers in a variety of cancers. This study investigated its clinical significance in a homogeneous group of lung cancer patients. Experimental Design: We analyzed the blood samples of 134 never smokers with advanced lung adenocarcinoma, who were enrolled in a prospective randomized phase III study (First-SIGNAL) comparing gefitinib with gemcitabine plus cisplatin (GP) as first-line therapy. The amount of plasma CFDNA was measured by real-time quantitative PCR targeting the human ACTB genomic sequence. The patients were divided into three groups according to the tertiles of baseline plasma CFDNA. Results: Baseline plasma CFDNA did not correlate with primary tumor size (P = 0.961), whereas the number of metastatic sites correlated significantly with baseline plasma CFDNA (P = 0.015). In the GP arm, the low-CFDNA group showed a lower response rate than the middle- or high-CFDNA group (26.1%, 57.9%, and 60.9%, respectively; P = 0.035). However, in the gefitinib arm, there was no difference in response rate between the three CFDNA groups (57.1%, 47.4%, and 51.9%; respectively; P = 0.825). The high tertile CFDNA group showed a significantly shorter survival than the low tertile CFDNA group (median overall survival, 16.0 vs. 28.6 months, respectively; P = 0.030). The risk of death increased with increased baseline plasma CFDNA (HR = 1.23, 95% CI, 1.01–1.50; P = 0.045). Conclusion: High plasma CFDNA is associated with aggressive tumor behavior and poor survival outcomes in these patients. Clin Cancer Res; 17(15); 5179–87. ©2011 AACR.

A phase II study of sunitinib in patients with relapsed or refractory small cell lung cancer

PURPOSEnThis study was conducted to evaluate the efficacy and safety of sunitinib in patients with relapsed or refractory small cell lung cancer (SCLC).nnnPATIENTS AND METHODSnEligibility included histologic or cytologic diagnosis of SCLC, ECOG PS of 0-2, cancer progression following one or two prior chemotherapy or chemo-radiotherapy (CRT) and adequate organ functions. Treatment regimen consisted of a 6-week cycle of sunitinib given as 50mg p.o. daily for 4 weeks followed by 2 weeks off. The primary end point was objective response rate (ORR).nnnRESULTSnFrom March 2008 to October 2010, 25 patients were enrolled and 24 received treatment. The median age was 64.5 years; 22 patients (92%) were male. Eight patients (33%) displayed sensitive relapse. Seven patients (29%) received CRT and fifteen patients (63%) had received one prior chemotherapy. A median of 1 cycle (range 1-4) of sunitinib was administered, and 23 patients were evaluable for response. Two patients displayed partial response, and seven patients presented stable disease with a ORR of 9% (95% CI, 1-28%). The median progression-free (PFS) and overall survivals were 1.4 months (95% CI, 1.1-1.7) and 5.6 months (95% CI, 3.5-7.7), respectively. The common grade 3 or 4 toxicities included thrombocytopenia (63%), asthenia (29%) and neutropenia (25%).nnnCONCLUSIONSnAlthough tumor response was noted in 2 patients, the median PFS was short and most patients were unable to tolerate the treatment. At the current dose schedule, sunitinib does not appear to warrant further evaluation.

Analysis of treatment outcomes of intraventricular chemotherapy in 105 patients for leptomeningeal carcinomatosis from non-small-cell lung cancer.

Introduction: Reports on the treatment result of leptomeningeal carcinomatosis (LMC) from a single primary cancer are rare and mixed treatment modalities make it even more difficult to interpret the results properly. Here, we report clinical outcomes of an intraventricular chemotherapy for LMC from non–small-cell lung cancer. Methods: Medical records of 105 patients were retrieved and retrospectively analyzed to find the prognostic factors of patients’ survival and symptom responses, including intracranial pressure (ICP) control. Results: There were 44 men and 61 women, with a median age of 56 years (range, 31–75 years). Patients received a median five rounds of intraventricular chemotherapy (range, 1–49 rounds). The most common presenting symptom was headache (77%) with nausea or vomiting, which showed the highest response rate of 42%. Altered mentality (36%), cranial neuropathy (15%), and cauda equina symptoms (12%) revealed 10% or less of symptom response. Only eight patients (7.6%) showed negative conversion of cerebrospinal fluid cytology. Median overall survival was 3.0 months (range, 0.5–21.5 months). Age (≥60 years), poor Karnofsky performance score (< 70), and uncontrolled ICP were found to be unfavorable prognostic factors for patient survival. A greater amount of intraventricular chemotherapy, which was evaluated as time-dependent covariate, and concurrent systemic chemotherapy significantly improved overall survival in the multivariable analysis. Conclusion: Intraventricular chemotherapy for patients with LMC from non–small-cell lung cancer could palliate associated symptoms and prolong patients’ survival. Careful selection of patients for intraventricular chemotherapy is recommended with aggressive ICP control and concurrent systemic chemotherapy.

A phase 2 study of irinotecan, cisplatin, and simvastatin for untreated extensive-disease small cell lung cancer.

The objective of this study was to investigate the efficacy of simvastatin in combination with irinotecan and cisplatin in chemotherapy‐naive patients with extensive‐disease small‐cell lung cancer (ED‐SCLC).

DNA repair gene polymorphisms and benefit from gefitinib in never-smokers with lung adenocarcinoma

The objective of this study was to investigate whether polymorphisms in DNA repair genes affect clinical outcome of never‐smokers with lung adenocarcinoma (NSLA).

Phase I/II study of gefitinib (Iressa®) and vorinostat (IVORI) in previously treated patients with advanced non-small cell lung cancer

PurposeVorinostat has been shown to overcome resistance to gefitinib. We performed a phase I/II study combining gefitinib with vorinostat in previously treated non-small cell lung cancer (NSCLC).MethodsA 3xa0+xa03 dose-escalation design was used to determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Three dose levels were tested: 250xa0mg/day gefitinib on days 1–28 and 200, 300 or 400xa0mg/day vorinostat on days 1–7, and 15–21 out of every 28xa0days. The primary endpoint was median progression-free survival (PFS).ResultsFifty-two patients were enrolled and treated (43 in phase II). The median age was 59xa0years, 28 patients were male, 44 had adenocarcinoma, 29 had never smoked, and 36 had undergone one prior treatment. Twenty-two patients exhibited sensitive EGFR mutations. Planned dose escalation was completed without reaching the MTD. The RP2D was 250xa0mg gefitinib and 400xa0mg vorinostat. In 43 assessable patients in phase II, the median PFS was 3.2xa0months; the overall survival (OS) was 19.0xa0months. There were 16 partial responses and six cases of stable disease. In EGFR-mutant NSCLC, response rate was 77xa0%, median PFS was 9.1xa0months, and median OS was 24.1xa0months. The most common adverse events were anorexia and diarrhea.ConclusionsTreatment with 250xa0mg gefitinib daily with biweekly 400xa0mg/day vorinostat was feasible and well tolerated. In an unselected patient population, this combination dose did not improve PFS. However, this combination showed a potential for improving efficacy of gefitinib in EGFR-mutant NSCLC (NCT01027676).