Bevacizumab Plus Erlotinib Combination Therapy for Advanced Hereditary Leiomyomatosis and Renal Cell Carcinoma-Associated Renal Cell Carcinoma: A Multicenter Retrospective Analysis in Korean Patients / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare genetic syndrome resulting from germline mutations in fumarate hydratase. The combination of bevacizumab plus erlotinib showed promising interim results for HLRCC-associated RCC. Based on these results, we analyzed the outcome of bevacizumab plus erlotinib in Korean patients with HLRCC-associated RCC. MATERIALS AND METHODS: We retrospectively reviewed the efficacy and safety of bevacizumab plus erlotinib in patients with HLRCC-associated RCC who were confirmed to have germline mutations in fumarate hydratase. The primary endpoint was the objective response rate (ORR), while the secondary endpoints were progression-free survival (PFS) and overall survival (OS). RESULT: We identified 10 patients with advanced HLRCC-associated RCC who received bevacizumab plus erlotinib. Median age at diagnosis was 41 years, and five of the patients had received the combination as first- or second-line treatments. The ORR was 50% and the median PFS and OS were 13.3 and 14.1 months, respectively. Most adverse events were predictable and manageable by conventional measures, except for one instance where a patient died of gastrointestinal bleeding. CONCLUSION: This is the first real-world outcome of the treatment of advanced HLRCC-associated RCC. Bevacizumab plus erlotinib therapy showed promising activity with moderate toxicity. We should be increasingly aware of HLRCC-associated RCC and bevacizumab plus erlotinib should be a first-line treatment for this condition, unless other promising data are published.

Investigating the Feasibility of Targeted Next-Generation Sequencing to Guide the Treatment of Head and Neck Squamous Cell Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is a deadly disease in which precision medicine needs to be incorporated. We aimed to implement next-generation sequencing (NGS) in determining actionable targets to guide appropriate molecular targeted therapy in HNSCC patients. MATERIALS AND METHODS: Ninety-three tumors and matched blood samples underwent targeted sequencing of 244 genes using the Illumina HiSeq 2500 platform with an average depth of coverage of greater than 1,000×. Clinicopathological data from patients were obtained from 17 centers in Korea, and were analyzed in correlation with NGS data. RESULTS: Ninety-two of the 93 tumors were amenable to data analysis. TP53 was the most common mutation, occurring in 47 (51%) patients, followed by CDKN2A (n=23, 25%), CCND1 (n=22, 24%), and PIK3CA (n=19, 21%). The total mutational burden was similar between human papillomavirus (HPV)–negative vs. positive tumors, although TP53, CDKN2A and CCND1 gene alterations occurred more frequently in HPV-negative tumors. HPV-positive tumors were significantly associated with immune signature-related genes compared to HPV-negative tumors. Mutations of NOTCH1 (p=0.027), CDKN2A (p < 0.001), and TP53 (p=0.038) were significantly associated with poorer overall survival. FAT1 mutations were highly enriched in cisplatin responders, and potentially targetable alterations such as PIK3CA E545K and CDKN2A R58X were noted in 14 patients (15%). CONCLUSION: We found several targetable genetic alterations, and our findings suggest that implementation of precision medicine in HNSCC is feasible. The predictive value of each targetable alteration should be assessed in a future umbrella trial using matched molecular targeted agents.

A Phase II Trial of Gemcitabine plus Capecitabine for Patients with Advanced Pancreatic Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of this study was to determine the efficacy and safety of treatment using gemcitabine and capecitabine for patients with advanced pancreatic cancer. MATERIALS AND METHODS: Patients with advanced unresectable pancreatic adenocarcinoma were enrolled in the study. Inclusion criteria included no prior systemic chemotherapy or radiation therapy, at least one radiographically documented and measurable tumor lesion, and adequate patient organ functions. The patients received 1,000 mg/m2 gemcitabine intravenously on days 1, 8 and 15, and 830 mg/m2 of oral capecitabine twice a day on days 1-21 of a 28-day cycle. RESULTS: Fifty patients with a median age of 53 years (range, 39 to 76 years) were enrolled in the study. The median follow-up was 10.0 months. The objective response rate of the 50 patients was 48.0% (95% CI, 22.5 to 57.1%). The median time to progression and overall survival were 6.5 months (95% CI, 2.3 to 8.7 months) and 10.0 months (95% CI, 5.7 to 16.7 months), respectively. Grade 3-4 toxicities associated with chemotherapy included neutropenia (22%), anemia (8%), thrombocytopenia (6%), and hand-foot syndrome (10%). CONCLUSION: Combination chemotherapy using gemcitabine and capecitabine was well tolerated and demonstrated promising efficacy in the treatment of advanced pancreatic cancer.

Effects of oral iron chelator deferasirox on human malignant lymphoma cells

BACKGROUND: Iron is essential for cell proliferation and viability. It has been reported that iron depletion by a chelator inhibits proliferation of some cancer cells. Deferasirox is a new oral iron chelator, and a few reports have described its effects on lymphoma cells. The goal of this study was to determine the anticancer effects of deferasirox in malignant lymphoma cell lines. METHODS: Three human malignant lymphoma cell lines (NCI H28:N78, Ramos, and Jiyoye) were treated with deferasirox at final concentrations of 20, 50, or 100 microM. Cell proliferation was evaluated by an MTT assay, and cell cycle and apoptosis were analyzed by flow cytometry. Western blot analysis was performed to determine the relative activity of various apoptotic pathways. The role of caspase in deferasirox-induced apoptosis was investigated using a luminescent assay. RESULTS: The MTT assay showed that deferasirox had dose-dependent cytotoxic effects on all 3 cell lines. Cell cycle analysis showed that the sub-G1 portion increased in all 3 cell lines as the concentration of deferasirox increased. Early apoptosis was also confirmed in the treated cells by Annexin V and PI staining. Western blotting showed an increase in the cleavage of PARP, caspase 3/7, and caspase 9 in deferasirox-treated groups. CONCLUSION: We demonstrated that deferasirox, a new oral iron-chelating agent, induced early apoptosis in human malignant lymphoma cells, and this apoptotic effect is dependent on the caspase-3/caspase-9 pathway.

No Association between Promoter Polymorphism of STK11 Gene and Lung Cancer Risk in the Korean Population / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Serine-threonine kinase11 (STK11) was originally identified in 1997 as the causative mutation that's responsible for Peutz-Jeghers Syndrome (PJS). Several recent studies have reported that the STK11 gene is an important human tumor suppressor gene in lung cancer. We evaluated the associations between the polymorphisms of the STK11 promoter region and the risk of lung cancer in 901 Koreans. MATERIALS AND METHODS: By direct sequencing, we first discovered three novel polymorphisms (-1,795 T>C, -981 C>T and -160 G>T) and four known polymorphisms (-1,580 C>T, -1,494 A>C, -881 A>G and -458 G>C) of the STK11 promoter region in 24 blood samples of 24 Korean lung cancer patients. Further genotype analyses were then performed on 443 lung cancer patients and 458 controls. RESULTS: We discovered three novel polymorphisms and we identified four known polymorphisms of the STK11 promoter region in a Korean population. Statistical analyses revealed that the genotypes and haplotypes in the STK11 gene were not significantly associated with the risk of lung cancer in a Korean population. CONCLUSION: This is the first study that's focused on the association of STK11 promoter polymorphisms and the risk of lung cancer in a Korean population. To evaluate the role of the STK11 gene for the risk of lung cancer, the genotypes of the STK11 promoter region (-1,795 T>C, -1,494 A>C and -160 G>T) were determined in 901 Koreans, yet the result revealed no significant difference between the lung cancer patients and the controls. These results suggest that the three promoter polymorphisms we studied are not important risk factors for the susceptibility to lung cancer in Koreans.

Reversible Posterior Leukoencephalopathy Syndrome in a Patient with Relapsed Hodgkin's Disease: A Case Report

Reversible posterior leukoencephalopathy syndrome (RPLS) is a distinctive clinicoradiological entity that's characterized by headache, confusion, seizure and frequent visual disturbances. It is associated with certain neuro-radiological findings, and predominantly white matter abnormalities of the parieto-occipital lobes. RPLS has been identified mostly in patients with malignant hypertension, pre-eclampsia and renal insufficiency and in those patients who are using immunosuppressive agents or cytotoxic drugs. We report here on a case of RPLS in a patient who was undergoing chemotherapy. A 49-year-old woman presented with abrupt mental changes and visual disturbances five days after the administration of a chemotherapeutic agent. MRI showed hyper-intense signals on the magnetic resonance (MR) diffusion images in the bilateral temporal, parietal and occipital lobes. The clinical manifestations completely resolved after one week of treatment that consisted of blood pressure control, a negative intake-output balance and the best supportive care. These radiological changes and the reversible clinical manifestations were consistent with RPLS.

A case of multiple myeloma recurred as skin involvement / 대한내과학회지

Multiple myeloma is a plasma cell disorder that constitutes 10% of all haematopoietc neoplasias. Although it is a systemic disorder affecting various organs involving bones and kidneys, skin involvement is a rare finding which has never been reported in Korea. Recently, we experienced a case of multiple myeloma recurring as a single lesion of erythematous nodular rash and herein we report this case with brief review of literatures.

A case of coronary arteriovenous malformation in variant angina patient / 대한내과학회지

Coronary arteriovenous malformation (AVM) is a rare congenital coronary anomaly. We report a 60 year-old woman with variant angina and coronary AVM. She presented with recurrent chest pain at rest but there were no significant cardiovascular risk factors. Baseline coronary angiography showed the AVM which originated from first diagonal branch. Acetylcholine (Ach) provocation test was performed at left anterior descending artery (LAD) to induce coronary spasm. Ach 50 microgram injection induced severe diffuse spasm at LAD with typical chest pain. We confirmed that this patient has variant angina with AV malformation.

Comparison of the Activities of Platelets with Different Cryopreservation Methods / 대한혈액학회지

BACKGROUND: The limit and the optimal method of the cryopreservation of platelets have not been determined. Moreover, the functional changes platelets after cryopreservation were not clearly defined. This study was conducted to determine the limit and optimal method for cryopreservation of platelet concentrates. METHODS: We compared the recovery, expression of membrane GpIb, GpIIb/IIIa, and aggregatory function of the platelets preserved in three different conditions. Platelet samples were collected from four healthy volunteer donors by apheresis, and placed in 22degrees C agitator for standard preservation. For cryopreservation, after treating 5% DMSO, platelets were either inserted directly in -80degrees C freezer or in liquid nitrogen after computer-controlled rate freezing. After storage for 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, and 12 weeks, platelets were thawed and analyzed for the evaluation of in vitro functions. RESULTS: Platelets preserved at 22degrees C or cryopreserved with each condition displayed equivalent recovery (90%). With each cryopreservation procedures, platelets showed moderate loss of GpIb and retained more than 90% of GpIIb/IIIa in comparison with fresh platelets. At the third week, loss of GpIb in the directly frozen platelets was augmented compared with those of controlled rate frozen group. The aggregatory response to ristocetin began to decrease drastically after storage for 5 days in platelets frozen by each procedures and to less than 5% at 12 weeks of storage. However, controlled rate frozen platelets retained more aggregatory response to ristocetin and surface GpIb expression than those of directly frozen platelets at 3, 4, 12 weeks of storage. CONCLUSION: This study showed the possibility of moderate preservation of in vitro functions of frozen-thawed platelets after 12 weeks of storage compared with those of the liquid stored 5-day old platelets.