Use of deferasirox, an iron chelator, to overcome imatinib resistance of chronic myeloid leukemia cells

BACKGROUND/AIMS: The treatment of chronic myeloid leukemia (CML) has achieved impressive success since the development of the Bcr-Abl tyrosine kinase inhibitor, imatinib mesylate. Nevertheless, resistance to imatinib has been observed, and a substantial number of patients need alternative treatment strategies. METHODS: We have evaluated the effects of deferasirox, an orally active iron chelator, and imatinib on K562 and KU812 human CML cell lines. Imatinib-resistant CML cell lines were created by exposing cells to gradually increasing concentrations of imatinib. RESULTS: Co-treatment of cells with deferasirox and imatinib induced a synergistic dose-dependent inhibition of proliferation of both CML cell lines. Cell cycle analysis showed an accumulation of cells in the subG1 phase. Western blot analysis of apoptotic proteins showed that co-treatment with deferasirox and imatinib induced an increased expression of apoptotic proteins. These tendencies were clearly identified in imatinib-resistant CML cell lines. The results also showed that co-treatment with deferasirox and imatinib reduced the expression of BcrAbl, phosphorylated Bcr-Abl, nuclear factor-kappaB (NF-kappaB) and beta-catenin. CONCLUSIONS: We observed synergistic effects of deferasirox and imatinib on both imatinib-resistant and imatinib-sensitive cell lines. These effects were due to induction of apoptosis and cell cycle arrest by down-regulated expression of NF-kappaB and beta-catenin levels. Based on these results, we suggest that a combination treatment of deferasirox and imatinib could be considered as an alternative treatment option for imatinib-resistant CML.

Population-Based Regional Cancer Incidence in Korea: Comparison between Urban and Rural Areas / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of this study is to investigate differences in organ-specific cancer incidence according to the region and population size in Korea. MATERIALS AND METHODS: We reviewed the data of the cancer registration program of Gyeongnam Regional Cancer Center between 2008 and 2011. Age-standardized rates of cancer incidence were analyzed according to population size of the region and administrative zone. RESULTS: Incidence of thyroid cancer has been increasing rapidly in both urban and rural areas. However, the thyroid cancer incidence was much lower in rural areas than in urban areas and megalopolis such as Seoul. Gastric cancer was relatively more common in rural areas, in megalopolis near the sea (Ulsan, Busan, and Incheon), and other southern provinces (Chungcheongnam-do, Gyeongsangbuk-do, and Gyeongsangnam-do). A detailed analysis in Gyeongsangnam-do revealed that rural areas have relatively low incidence of thyroid and colorectal cancer, and relatively high incidence of gastric and lung cancer compared to urban areas. CONCLUSION: This study suggests that there are some differences in cancer incidence by population size. Thyroid and colorectal cancer incidence was increasing, and gastric and lung cancer was slightly decreasing in urban areas, whereas gastric and lung cancer incidence still remains high in rural areas.

Concurrent Chemoradiation with Low-Dose Weekly Cisplatin in Locally Advanced Stage IV Head and Neck Squamous Cell Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Concurrent chemoradiation (CRT) with 3-weekly doses of cisplatin is a standard treatment for loco-regionally advanced head and neck squamous cell carcinoma (HNSCC). However, treatment with 3-weekly doses of cisplatin is often associated with several adverse events. Therefore, we conducted this retrospective analysis to determine the efficacy and tolerance of CRT with a low weekly dose of cisplatin in stage IV HNSCC patients. MATERIALS AND METHODS: Medical records of patients who were diagnosed with stage IV HNSCC and received concurrent CRT were analyzed. All patients were treated weekly with cisplatin at 20-30 mg/m2 until radiotherapy was completed. RESULTS: A total of 35 patients were reviewed. Median follow up was 10.7 months (range, 1.7 to 90.5 months), the median radiation dose was 7,040 cGy, and the median dose of cisplatin received was 157 mg/m2. Eleven patients received docetaxel combination chemotherapy. Overall, 25 patients (71.4%) achieved complete response (CR), eight (22.9%) showed partial response. The median overall survival was 42.7 months, the 3-year survival rate was 51.2% and the 3 year disease-free survival rate was 72.8%. Overall survival was improved in patients who achieved CR relative to others (59.7 months vs. 13.4 months; p=0.008). There were significant differences in survival between patients who received docetaxel combination and cisplatin alone (51.8 months vs. 7.9 months; p=0.009). Grade 3-4 adverse events included stomatitis (82.9%), dermatitis (22.9%), infection (11.4%), dysphagia (8.6%), and neutropenia (5.7%). CONCLUSION: CRT with low dose weekly cisplatin is likely effective and tolerable, even in patients with locally advanced-stage IV HNSCC.

Effect of early chemoradiotherapy in patients with limited stage small cell lung cancer

PURPOSE: We evaluated the effect of early chemoradiotherapy on the treatment of patients with limited stage small cell lung cancer (LS-SCLC). MATERIALS AND METHODS: Between January 2006 and December 2011, thirty-one patients with histologically proven LS-SCLC who were treated with two cycles of chemotherapy followed by concurrent chemoradiotherapy and consolidation chemotherapy were retrospectively analyzed. The chemotherapy regimen was composed of etoposide and cisplatin. Thoracic radiotherapy consisted of 50 to 60 Gy (median, 54 Gy) given in 5 to 6.5 weeks. RESULTS: The follow-up period ranged from 5 to 53 months (median, 22 months). After chemoradiotherapy, 35.5% of the patients (11 patients) showed complete response, 61.3% (19 patients) showed partial response, 3.2% (one patient) showed progressive disease, resulting in an overall response rate of 96.8% (30 patients). The 1-, 2-, and 3-year overall survival (OS) rates were 66.5%, 41.0%, and 28.1%, respectively, with a median OS of 21.3 months. The 1-, 2-, and 3-year progression free survival (PFS) rates were 49.8%, 22.8%, and 13.7%, respectively, with median PFS of 12 months. The patterns of failure were: locoregional recurrences in 29.0% (nine patients), distant metastasis in 9.7% (three patients), and both locoregional and distant metastasis in 9.7% (three patients). Grade 3 or 4 toxicities of leukopenia, anemia, and thrombocytopenia were observed in 32.2%, 29.0%, and 25.8%, respectively. Grade 3 radiation esophagitis and radiation pneumonitis were shown in 12.9% and 6.4%, respectively. CONCLUSION: We conclude that early chemoradiotherapy for LS-SCLC provides feasible and acceptable local control and safety.

Inefficiency in 6-Set Requests for Blood Culture Analysis of Cancer Patients with the Central Venous Catheter

BACKGROUND: A central venous catheter (CVC) is commonly used for administering chemotherapy to cancer patients. The institutional guideline of the Gyeongsang National University Hospital (GNUH) for blood culture analysis of indwelling CVC patients recommended 6 sets (2 from the periphery and 4 from each lumen). We analyzed the usefulness of this guideline, because complying with this recommendation requires an abundant amount of the sample and it is both inconvenient and expensive. METHODS: Adult patients (age: > or =18 yr old) who were admitted to the cancer center of GNUH between January 2011 and April 2012 were requested to have their blood culture analysis done. The positive rate, contamination rate, and distribution of microorganisms were compared according to the number of requested sets. The positive results of the stipulated 6 sets were analyzed. RESULTS: A total of 5,263 blood cultures were analyzed during the study period; of them, 74.4% were requests of 2 sets and 20.0% were requests of 6 sets. The positive rates in 2 set requests and 6 set requests were 8.0% and 14.3%, respectively (P<0.001). The requests for 6 sets were repeated about 5 times. All 6 sets showed positive in 16 cases (9.1%), whereas a part of the 6 sets was positive in 18 cases (10.3%). CONCLUSIONS: Although the positive rate was relatively high in the 6 set-requested groups, they had to be repeatedly requested. Microbial growth in a part of the 6-set requests was observed in a very small proportion (10.3%) of the patients, indicating that the benefit of blood culture of 6 sets is very low.

Assessment of the Effect of a Public Health Clinics' Home-Based Terminal Cancer Patient Management in Collaboration with a Regional Cancer Center / 한국호스피스완화의료학회지

PURPOSE: Home-based care providers were surveyed to assess the effect of collaborative service between Gyeongnam Regional Cancer Center (GRCC) and public health centers (PHCs) in Gyeongnam province. METHODS: Twenty home-based care providers who had previously participated in the GRCC-PHC care project were recruited from nine PHCs and were surveyed using a questionnaire developed by specialists. Questions were rated using the 5-point Likert scale ranging from "strongly disagree (-2)" to "strongly agree (+2)" and each score was multiplied by the corresponding number of respondents (n=20) with the maximum score of 40. RESULTS: Between January 2008 and December 2011, 73 patients were registered to the collaborative service: 72 by GRCC and one by PHC. Home-based care providers marked the highest score (23 points) to "The collaborative service contributed to patients and their family's psychological stability" and the lowest score (11 points) to "The collaborative service was generally helpful for home-based cancer management." For possible suggestions to improve the service, the highest score (35 points) was given to "Simplification of the hospitalization process" followed by "Substantial benefits for patients at their visit to the hospital" (34 points). CONCLUSION: The results revealed several limitations of the GRCC-PHC collaborative care service for terminal cancer patients. The service could be further improved by developing measures to address the limitations and a service model tailored to region-specific needs.

Concurrent chemoradiotherapy for elderly patients with stage III non-small cell lung cancer

PURPOSE: Combined chemoradiotherapy is standard management for locally advanced non-small cell lung cancer (LA-NSCLC), but standard treatment for elderly patients with LA-NSCLC has not been confirmed yet. We evaluated the feasibility and efficacy of concurrent chemoradiotherapy (CCRT) for elderly patients with LA-NSCLC. MATERIALS AND METHODS: Among patients older than 65 years with LA-NSCLC, 36 patients, who underwent CCRT were retrospectively analyzed. Chemotherapy was administered 3-5 times with 4 weeks interval during radiotherapy. Thoracic radiotherapy was delivered to the primary mass and regional lymph nodes. Total dose of 54-59.4 Gy (median, 59.4 Gy) in daily 1.8 Gy fractions and 5 fractions per week. RESULTS: Regarding the response to treatment, complete response, partial response, and no response were shown in 16.7%, 66.7%, and 13.9%, respectively. The 1- and 2-year overall survival (OS) rates were 58.2% and 31.2%, respectively, and the median survival was 15 months. The 1- and 2-year progression-free survivals (PFS) were 41.2% and 19.5%, respectively, and the median PFS was 10 months. Regarding to the toxicity developed after CCRT, pneumonitis and esophagitis with grade 3 or higher were observed in 13.9% (5 patients) and 11.1% (4 patients), respectively. Treatment-related death was not observed. CONCLUSION: The treatment-related toxicity as esophagitis and pneumonitis were noticeably lower when was compared with the previously reported results, and the survival rate was higher than radiotherapy alone. The results indicate that CCRT is an effective in terms of survival and treatment related toxicity for elderly patients over 65 years old with LA-NSCLC.

Outcomes of Third-Line Docetaxel-Based Chemotherapy in Advanced Gastric Cancer Who Failed Previous Oxaliplatin-Based and Irinotecan-Based Chemotherapies / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Little is known about outcomes in the use of third-line chemotherapy in cases of advanced gastric cancer (AGC). The primary aim of this retrospective study was to evaluate outcomes of docetaxel-based chemotherapy in patients with AGC that progressed after both oxaliplatin-based and irinotecan-based regimens. MATERIALS AND METHODS: Eligible patients were those with AGC who had previous chemotherapy including fluoropyrimidine and oxaliplatin as well as fluoropyrimidine and irinotecan and who received subsequent docetaxel-based chemotherapy. Thirty-five patients were retrospectively recruited from 5 medical centers in Korea. Patients received either weekly or 3 weekly with docetaxel +/- cisplatin. RESULTS: Thirty-one out of 35 patients were evaluated for treatment response. A total of 94 cycles of chemotherapy (median, 2; range, 1 to 7) were administered. The overall response rate was 14.3%, and the disease control rate was 45.7%. The median progression-free survival (PFS) was 1.9 months (95% confidence interval [CI], 1.1 to 2.7 months). The median overall survival (OS) was 3.6 months (95% CI, 2.8 to 4.4 months). PFS and OS were significantly prolonged in patients of the Eastern Cooperative Oncology Group, with performance status of 0 or 1 in multivariate analysis (PFS: hazard ratio[HR], 0.411; 95% CI, 0.195 to 0.868; p=0.020 and OS: HR, 0.390; 95% CI, 0.184 to 0.826; p=0.014, respectively). Four of the 35 patients enrolled in the study died due to infection associated with neutropenia. CONCLUSION: Our findings suggest that salvage docetaxel-based chemotherapy is a feasible treatment option for AGC patients with good performance status (PS), whereas chemotherapy for patients with poor PS (PS< or =2) should be undertaken with caution for those who previously failed oxaliplatin- and irinotecan-based regimens.

Successful Treatment of Syncope with Chemotherapy Irresponsive to Cardiac Pacemaker in Head and Neck Cancer

Recurrent syncope as a complication of recurrent neck malignancy is an uncommon but well documented association. The syncope is presumed to occur when a tumor mass invades the baroreceptor within the carotid sinus or when it disrupts the afferent nerve fibers of the glossopharyngeal nerve. A 59-year-old man presented with recurrent syncope and headache. He had a wide local excision including tonsillectomy and modified left radical neck dissection for tonsilar cancer 4 years ago. A computed tomography scan revealed ill-defined lesions in left parapharyngeal, carotid space and right upper jugular region. After clinical evaluation, cardiac pacemaker was placed, but he still suffered from the syncope. Then, he received the chemotherapy with docetaxel and cisplatin. The last hypotension event occurred on day 10 of the chemotherapy. Six months after 3 cycles of chemotherapy, he remained in complete remission and resolution of syncope. We report a case in which syncope was associated with a recurrence of tonsilar cancer and successfully treated with chemotherapy.

A Case of Angio-invasive Pulmonary Mucormycosis with Uncontrolled Diabetes Mellitus / 결핵및호흡기질환

Pulmonary mucormycosis is an uncommon, serious opportunistic infection caused by fungi belonging to the order Mucorales and it occurs exclusively in debilitated or immuno-compromised hosts. It is known that the fungi can invade the blood vessels and cause serious ischemic necrosis and bleeding5. We experienced a fatal case of pulmonary mucormycosis in a diabetic 75-year-old man who developed a progressive necrotizing lesion despite administering proper and prompt medical and surgical treatment. We report here on this case along with a review of the relevant medical literature.

Irreversible Paraplegia Following One Time Prophylactic Intrathecal Chemotherapy in an Adult Patient with Acute Lymphoblastic Leukemia

We present an adult female patient who developed irreversible paraplegia and areflexia four days post intrathecal chemotherapy with methotrexate, cytosine arabinoside and hydrocortisone. On magnetic resonance imaging (MRI) of the lumbar spine, diffuse gadolinium enhancement of the anterior spinal nerve roots (ventral roots) was detected. Methylprednisolone was intravenously administered at a daily dose of 30mg/kg for three days. Despite this treatment, flaccid weakness in the lower extremities and urinary retention persisted. Following consolidation chemotherapy, no improvement in neurologic status was noted. Six months later, a follow-up MRI revealed severe atrophy of the thoracic spinal cord.

Oxidative Stress of Mouse Fed Irradiated Diet Containing High Unsaturated Fatty Acid

In this study, we investigated the in vivo effect by intake of the irradiated foods such as mackerel and sesame seed which are high in unsaturated fatty acid through TBARS (thiobarbituric acid reactive subtance) and the tissue pathological and genotoxicological test. Thirty two ICR mice are divided into four groups, one non-irradiated (control) group and three irradiated (5, 10, 20 kGy, respectively) groups. Sesame seed and pulverized mackerel in modified AIN93M diet were mixed together then divided into four identical parts. Three parts of them were irradiated by doses of 5, 10, and 20 kGy. These experimental diet were fed to each group for 4, 8 and 16 weeks. The results of the study were as follows: No significant differences in weight gain were found in each group. Peroxide value of the irradiated diet was higher than that of the non-radiated one and also increased according to the storage period. TBA values in plasma, liver, kidney and Peyer's patch were not significantly different among 4 groups. DNA% in tail, tail length (TL) and tail moment (TM) values of the blood lymphocyte in 4, 8 and 16 week groups and the liver in 16 week group were much measured over the control. DNA% in tail of kidney of 8 week group was significantly larger than the control and TL and TM of 8 week and TM of 16 week groups showed a tendency of higher values. By Peyer's patch, DNA% in tail of 8 week group, DNA% in tail and TM of 16 week groups increased significantly over the control. Ultrastructural examination shows myeline figures and swollen mitochondria in parietal cells and intestinal epithelial cells of 8 and 16 weeks groups. After this study, we need further investigations on the safety of highly consumed foods which contai high contents of unsaturated fatty acid, largely imported and which are possible to be irradiated.