Seong Yoon Yi

ERCC1 expression as a predictive marker of squamous cell carcinoma of the head and neck treated with cisplatin-based concurrent chemoradiation.

The excision repair cross-complementation group 1 (ERCC1) enzyme plays a rate-limiting role in the nucleotide excision repair pathway and is associated with resistance to platinum-based chemotherapy. The purpose of this study was to evaluate the role of ERCC1 expression as a predictive marker of survival in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) treated with cisplatin-based concurrent chemoradiotherapy (CCRT). ERCC1 expression was assessed by immunohistochemical staining. The median age of the 45 patients analysed was 56 years (range 27–75 years), and 82% were men; 73% of all specimens showed high expression of ERCC1. The overall tumour response rate after CCRT was 89%. The median follow-up was 53.6 months (95% CI, 34.5–72.7 months). The 3-year progression-free survival (PFS) and overall survival (OS) rates were 58.7 and 61.3%, respectively. Univariate analyses showed that patients with low expression of ERCC1 had a significantly higher 3-year PFS (83.3 vs 49.4%, P=0.036) and OS (91.7 vs 45.5%, P=0.013) rates. Multivariate analysis showed that low expression of ERCC1 was an independent predictor for prolonged survival (HR, 0.120; 95% CI, 0.016–0.934, P=0.043). These results suggest that ERCC1 expression might be a useful predictive marker of locally advanced SCCHN in patients treated with cisplatin-based CCRT.

Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients

In patients with human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer, treatment with trastuzumab has been shown to markedly improve the outcome. We investigated the role of trastuzumab on brain metastasis (BM) in HER2-positive breast cancer patients. From 1999 to 2006, 251 patients were treated with palliative chemotherapy for HER2-positive metastatic breast cancer at Samsung Medical Center. The medical records of these patients were analysed to study the effects of trastuzumab on BM prevalence and outcomes. Patients were grouped according to trastuzumab therapy: pre-T (no trastuzumab therapy) vs post-T (trastuzumab therapy). The development of BM between the two treatment groups was significantly different (37.8% for post-T vs 25.0% for pre-T, P=0.028). Patients who had received trastuzumab had longer times to BM compared with patients who were not treated with trastuzumab (median 15 months for post-T group vs 10 months for pre-T group, P=0.035). Time to death (TTD) from BM was significantly longer in the post-T group than in the pre-T group (median 14.9 vs 4.0 months, P=0.0005). Extracranial disease control at the time of BM, 12 months or more of progression-free survival of extracranial disease and treatment with lapatinib were independent prognostic factors for TTD from BM.

Clinical Outcome of Gastric Cancer Patients with Bone Marrow Metastases

Background: Gastric cancer with bone marrow metastases is known to pursue a rapidly deteriorating clinical course. We conducted a retrospective analysis to evaluate clinical manifestations and prognosis of gastric cancer patients with bone marrow metastases. Methods: Between September 1994 and February 2006, 39 gastric cancer patients with pathologically confirmed bone marrow dissemination were selected. Results: The majority of the patients showed younger age, poorly differentiated adenocarcinoma or signet ring cell carcinoma, thrombocytopenia, anemia, elevated lactate dehydrogenase and alkaline phosphatase. Poor prognostic factors for survival were serum sodium ≤133 mmol/l [relative risk (RR) 4.57; 95% CI 1.99–10.52; p < 0.001], the presence of lung metastasis (RR 3.47; 95% CI 1.48–8.15; p = 0.007) and the presence of peritoneal seeding (RR 2.17; 95% CI 1.06–4.43; p = 0.036). Median survival durations after bone marrow metastases for patients without any adverse factors (n = 19, 48.7%) and those with 1–3 adverse factors (n = 20, 51.3%) were 67 and 23 days, respectively (p = 0.013). Patients without any adverse factors did benefit from palliative chemotherapy (p = 0.048). Conclusion: We suggest that gastric cancer patients with bone marrow metastases should receive more tailored therapies according to different risk factors in order to enhance survival.

Dacarbazine-based chemotherapy as first-line treatment in noncutaneous metastatic melanoma: multicenter, retrospective analysis in Asia.

Malignant melanoma, a neoplastic disorder produced by malignant transformation of the melanocyte, is considered to be resistant to chemotherapy. Dacarbazine is one of the standard chemotherapeutic agents in Korea. This study is designed to analyze treatment outcome and delineate prognostic factors based on clinical parameters for patients with advanced malignant melanoma who had received dacarbazine-based chemotherapy. This is a multicenter, retrospective analysis of 95 patients with metastatic malignant melanoma who had received dacarbazine-based chemotherapy, from January 1997 to June 2010. After a median follow-up duration of 41 months (range, 2–191 months), median survival time from the start of treatment was 12.1 months [95% confidence interval (CI): 10.9–13.5]. The overall response rate was 26.3% (95% CI: 17.8–36.4). On univariate analysis, primary site [mucosa of head and neck, gastrointestinal (GI)/genitourinary tract > cutaneous+acral melanoma], metastases to liver, GI tract, and elevated lactate dehydrogenase adversely influenced on survival. At a multivariate level, independent poor prognostic factors were mucosal melanoma [P=0.001; hazard ratio (HR): 2.988; 95% CI: 1.534–5.821], metastasis to GI tract [P=0.040; HR: 2.108; 95% CI: 1.036–4.288], and elevated lactate dehydrogenase (P=0.047; HR: 1.695; 95% CI: 1.007–2.854). Dacarbazine-based chemotherapy seems to be a reasonable option in Asia where mucosal melanoma is more prevalent than in the West. The dacarbazine-based chemotherapy showed an overall response rate of 26.3% and an overall survival of 12.1 months without a significant difference in response rates between noncutaneous or cutnaeous melanoma.

Excision repair cross‐complementation group 1 (ERCC1) expression in advanced urothelial carcinoma patients receiving cisplatin‐based chemotherapy

Kim KH, Do I‐G, Kim HS, Chang MH, Kim HS, Jun HJ, Uhm J, Yi SY, Lim DH, Ji SH, Park MJ, Lee J, Park SH, Kwon GY, Lim HY. Excision repair cross‐complementation group 1 (ERCC1) expression in advanced urothelial carcinoma patients receiving cisplatin‐based chemotherapy. APMIS 2010; 118: 941–8.

The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma

Deletion of CDKN2A (p16) or amplification of CCND1 (cyclin D1) occurs commonly in head and neck squamous cell carcinoma (HNSCC) and induces sustained cyclin-dependent kinase (CDK) 4/6 activation. Here, we report the antiproliferative activity of LY2835219, a selective CDK4/6 inhibitor through inhibition of CDK4/6-dependent Ser780 phosphorylation in retinoblastoma (RB) and induction of cell cycle arrest in HNSCC cells. In addition, we demonstrated the antitumor effects of HNSCC xenografts to LY2835219 in vivo. Given the limited effect in HNSCC as a single-agent treatment with LY2835219, a combinational strategy is required to enhance antitumor activity. At the molecular level, we found that LY2835219 inhibited activation of AKT and ERK, but not mTOR. The combination of LY2835219 with mTOR inhibitor was found to be more effective than either drug alone in vitro and in vivo. Taken together, our findings suggest that a combinational treatment with LY2835219 and mTOR inhibitor is a promising therapeutic approach for HNSCC.

Comparison of survival in advanced non-small cell lung cancer patients in the pre- and post-gefitinib eras.

Background: The aim of this study was to analyze the survival difference between advanced non-small cell lung cancer (NSCLC) patients in the pre-gefitinib and post-gefitinib eras in Korea. Patients and Methods: 830 patients with advanced/metastatic or recurrent NSCLC who received palliative chemotherapy were retrospectively reviewed. Using a matched-pair case-control study design, 334 pairs from the pre-gefitinib era (January 1999 to December 2001) and the post-gefitinib era (January 2002 to December 2005) were matched by age, sex and histology. Results: The median overall survival from the date of first administration of palliative chemotherapy was significantly longer in the post-gefitinib era (11.5 vs. 19.3 months, p< 0.001). Multivariate analysis showed that gefitinib was associated with longer overall survival (hazard ratio 0.58, p< 0.001) as were never having been a smoker, adenocarcinoma histology, good performance, stage IIIB, ≥3 prior episodes of chemotherapy, platinum-based chemotherapy and previous docetaxel or pemetrexed treatment. Patients in the post-gefitinib era showed significantly longer overall survival in almost all subgroups. Gefitinib treatment was of significantly greater benefit in patients with adenocarcinoma than in those with non-adenocarcinoma (test for interaction p< 0.001). Conclusion: These results indicate a significant improvement of survival in advanced NSCLC patients treated with gefitinib in Korea.

L1 cell adhesion molecule as a predictor for recurrence in pulmonary carcinoids and large-cell neuroendocrine tumors

Pulmonary neuroendocrine tumors are a distinct subset of neoplasms with indolent to aggressive behavior. This study was conducted to evaluate the prognostic role of L1 cell adhesion molecule (L1CAM) in pulmonary neuroendocrine tumors. We retrospectively analyzed L1 expression in 55 cases of completely resected carcinoids and large‐cell neuroendocrine carcinomas, by the immunohistochemistry with monoclonal antibody A10‐A3 against human L1. L1 immunoreactivity was detected in 34 (61.8%) of 55 specimens. There was a significant correlation between L1 expression and the World Health Organization classification of this tumor (Spearman rank correlation, ρ=0.60, p<0.001). With median follow‐up of 52.0 months, the 5‐year survival rate for patients with low expression of L1 (<20% of tumor cells stained) was significantly better compared with those with high expression of L1 (82.6% vs. 43.7%, p=0.005). L1 was also a significant independent predictor of disease‐free survival, and patients with high L1 expression have a higher risk for recurrence compared with those with low L1 expression (hazard ratio, 3.0; 95% confidence interval, 1.2–8.3; p=0.034). L1 expression is significantly associated with aggressiveness and further studies with larger samples are needed to validate potential prognostic value for pulmonary neuroendocrine tumors.

Evaluation of Prescribing Medications for Terminal Cancer Patients near Death: Essential or Futile.

Purpose The purpose of this study is to evaluate the prescription of essential or futile medications for terminal cancer patients during their final admission. Materials and Methods We conducted a retrospective review of the medical charts of terminally ill cancer patients admitted to the Hemato-oncology Department of two teaching hospitals from March 1, 2007 to December 31, 2009. Essential medications were based on the drugs listed by the International Association for Hospice and Palliative Care, while futile medications were defined when short-term benefit to patients with respect to survival, quality of life, or symptom control was not anticipated. Results A total of 196 patients were included. Among essential medications, strong opioids were the most frequently prescribed drugs during the last admission (62.2% fentanyl, 44.3% morphine), followed by megestrol (46.0%), and metoclopramide (37.2%); 51% of gastric protectors were prescribed with potential futility. Anti-hypertensive and antiglycemic agents were administered to those who experienced arterial blood pressure below 90 mm Hg (47.3%) or presented with a single measurement of fasting glucose below 50 mg/dL (10.7%), respectively. Statins were prescribed to 6.1% (12/196) of patients, and 75% of those prescriptions were regarded as futile. Conclusion Our data suggest that effective prescription of essential medications and withdrawal from futile medications should be actively reconciled for improvement of a patients end-of-life care.

Depletion of l-ascorbic acid alternating with its supplementation in the treatment of patients with acute myeloid leukemia or myelodysplastic syndromes

Purpose:  l‐ascorbic acid (LAA) modifies the in vitro growth of leukemic cells from ∼50% of patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). To test the hypothesis that depletion of LAA, alternating with supplementation to prevent scurvy, would provide therapeutic benefit, a single‐arm pilot trial was conducted (ClinicalTrials.gov identifier: NCT00329498).