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Background: In this study, we prepared and evaluated an injectable poloxamer (P407) hydrogel formulation for intratympanic (IT) delivery of dexamethasone (DEX)., Methods: DEX-loaded P407 hydrogels were characterized in terms of thermogelation, drug loading capacities, particle size, and drug release. The in vivo toxicity and drug absorption of the DEX-loaded P407 formulation after IT injection were evaluated using an animal model by performing histopathological analysis and drug concentration measurements., Results: The P407 hydrogel effectively solubilized hydrophobic DEX and demonstrated a sustained release compared to the hydrophilic DEX formulation. The in vivo study showed that the hydrogel formulation delivered considerable drug concentrations to the inner ear and displayed a favorable safety profile without apparent cytotoxicity or inflammation., Conclusion: P407 hydrogel can be useful as an injectable inner ear delivery formulation for hydrophobic drugs due to their biocompatibility, drug-solubilizing capacity, thermogelation, and controlled release., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Background: Obesity is an independent risk factor for hearing loss. Although attention has focused on major obesity comorbidities such as cardiovascular disease, stroke, and type 2 diabetes, the impact of obesity on sensorineural organs, including the auditory system, is unclear. Using a high-fat diet (HFD)-induced obese mouse model, we investigated the impact of diet-induced obesity on sexual dimorphism in metabolic alterations and hearing sensitivity., Methods: Male and female CBA/Ca mice were randomly assigned to three diet groups and fed, from weaning (at 28 days) to 14 weeks of age, a sucrose-matched control diet (10 kcal% fat content diet), or one of two HFDs (45 or 60 kcal% fat content diets). Auditory sensitivity was evaluated based on the auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE), and ABR wave 1 amplitude at 14 weeks of age, followed by biochemical analyses., Results: We found significant sexual dimorphism in HFD-induced metabolic alterations and obesity-related hearing loss. Male mice exhibited greater weight gain, hyperglycemia, increased ABR thresholds at low frequencies, elevated DPOAE, and lower ABR wave 1 amplitude compared to female mice. The hair cell (HC) ribbon synapse (CtBP2) puncta showed significant sex differences. The serum concentration of adiponectin, an otoprotective adipokine, was significantly higher in female than in male mice; cochlear adiponectin levels were elevated by HFD in female but not male mice. Adiponectin receptor 1 (AdipoR1) was widely expressed in the inner ear, and cochlear AdipoR1 protein levels were increased by HFD, in female but not male mice. Stress granules (G3BP1) were significantly induced by the HFD in both sexes; conversely, inflammatory (IL-1β) responses were observed only in the male liver and cochlea, consistent with phenotype HFD-induced obesity., Conclusions: Female mice are more resistant to the negative effects of an HFD on body weight, metabolism, and hearing. Females showed increased peripheral and intra-cochlear adiponectin and AdipoR1 levels, and HC ribbon synapses. These changes may mediate resistance to HFD-induced hearing loss seen in female mice., (© 2023. The Author(s).)

Purpose: Although many studies have examined the efficiency of various protective devices for reducing the dose of radiation exposure to physicians during interventional pain procedures, no study has compared the protective effect of these devices when they are used in combination. The purpose of this prospective experimental study was to determine the best combination of radiation-shielding devices., Materials and Methods: Using anthropomorphic phantoms of a physician and patient, we measured the radiation protection efficiency (RPE) of each of the following protection methods and in combination during C-arm-guided simulated lumbar epidural injection: (a) personal protective equipment (PPE), (b) bedside curtain shield (Curtain), (c) x-ray tube filter (Filter), and (d) fluoroscopic collimation method (Collimation). We measured exposure doses using personal electronic dosimeters at the eye, thyroid, and gonad levels for 1 minute. Each experiment was repeated 15 times., Results: The radiation exposure dose and RPE with the best single-, double-, and triple-protection methods were as follows: PPE for the single-protection method (11.82 μSv/min, 80.04%), PPE + Collimation for the double-combination method (4.68 μSv/min, 92.09%), and PPE + Collimation + Curtain for the triple-combination method (3.08 μSv/min, 93.39%). Additionally, PPE + Collimation + Curtain + Filter for the quadruple-combination method resulted in a radiation exposure and RPE of 2.91 μSv/min and 93.61%, respectively, compared with nonprotection., Conclusions: The best single-, double-, and triple-protection method was PPE, PPE + Collimation, and PPE + Collimation + Curtain, respectively. While preparing protective equipment, we recommend prioritizing equipment in this order., (Copyright © 2021 SIR. Published by Elsevier Inc. All rights reserved.)

We prepared a new injectable thermogel to enhance the efficiency of inner ear delivery of dexamethasone (DEX). Hexanoyl glycol chitosan (HGC) was synthesized and evaluated as an amphiphilic thermogel (T gel  ~ 32 °C) for use as a solubilizing agent as well as an injectable carrier for intratympanic delivery of the hydrophilic and hydrophobic forms of DEX. Various thermogel formulations with different drug types and concentrations were prepared, and their physicochemical and thermogelling properties were characterized by 1 H NMR, ATR-FTIR, and rheometer. They exhibited versatile release kinetics from several hours to more than 2 weeks, depending on drug type and concentration. Our formulations further showed good residual stability for more than 21 days without any cytotoxicity or inflammation in the middle and inner ear and could deliver a considerably high drug concentration into the inner ear. Therefore, HGC thermogel has great potential as an effective and safe formulation for inner ear drug delivery., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Although previous studies continuously report an increased risk of hearing loss in diabetes patients, the impact of the disease on the inner ear remains unexplored. Herein, we examine the pathophysiology of diabetes-associated hearing impairment and cochlear synaptopathy in a mouse model of diabetes. Male B6.BKS(D)- Lepr db /J (db/db, diabetes) and heterozygote (db/+, control) mice were assigned into each experimental group (control vs. diabetes) based on the genotype and tested for hearing sensitivity every week from 6 weeks of age. Each cochlea was collected for histological and biological assays at 14 weeks of age. The diabetic mice exerted impaired hearing and a reduction in cochlear blood flow and C-terminal-binding protein 2 (CtBP2, a presynaptic ribbon marker) expression. Ultrastructural images revealed severely damaged mitochondria from diabetic cochlea accompanied by a reduction in Cytochrome c oxidase subunit 4 (COX4) and CR6-interacting factor 1 (CRIF1). The diabetic mice presented significantly decreased levels of platelet endothelial cell adhesion molecule (PECAM-1), B-cell lymphoma 2 (BCL-2), and procaspase-9, but not procaspase-8. Importantly, significant changes were not found in necroptotic programmed cell death markers (receptor-interacting serine/threonine-protein kinase 1, RIPK1; RIPK3; and mixed lineage kinase domain-like pseudokinase, MLKL) between the groups. Taken together, diabetic hearing loss is accompanied by synaptopathy, microangiopathy, damage to the mitochondrial structure/function, and activation of the intrinsic apoptosis pathway. Our results imply that mitochondrial dysfunction is deeply involved in diabetic hearing loss, and further suggests the potential benefits of therapeutic strategies targeting mitochondria.

The objective of this study was to investigate functional abnormalities of the brain in a patient with multiple sclerosis (MS) by using magnetoencephalography (MEG) and a finger-tapping task. A 46-year-old woman that presented with motor weakness of left hand and was diagnosed with MS. Conventional magnetic resonance imaging demonstrated a white matter lesion with hyperintensity on T2-weighted images in the right motor area. MEG recordings were performed during the period of motor weakness and after clinical improvement. Neuromagnetic brain activation was elicited by a simple, visually cued finger movement. The Equivalent current dipole (ECD) strength of the movement-evoked field (MEF) in the affected hemisphere was significantly decreased relative to the unaffected hemisphere. After improvement in motor weakness, we found that the lower amplitude of the readiness field and decreased ECD strength of the MEF observed in affected hemisphere during motor weakness had recovered. Analysis of motor-related neuromagnetic fields revealed that MEG may be used to detect diffuse changes in the brain that are not observable by conventional imaging of white matter regions in MS. We further found that brain activities can change after improvement in motor weakness., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Monoclonal antibodies and other biologic drugs play important roles in the treatment of various hematological malignancies and solid tumors. However, such drugs are intrinsically more expensive to develop than small molecules and their clinical benefits are often accompanied by challenges relating to affordability and access. Patent expiry for 'originator' biologics is providing opportunities for a new generation of biosimilar drugs, potentially capable of relieving pressure on healthcare budgets. This article discusses key characteristics of biosimilars, distinguishes them from generics and noncomparable biologics and outlines the robust regulatory requirements that must be followed to establish biosimilarity with a reference product. The path to approval is discussed with reference to the rituximab biosimilar CT-P10, the first licensed monoclonal antibody biosimilar cancer therapeutic.

As the patents for many biologic anticancer drugs expire, significant growth in the use of biosimilars is predicted, offering an opportunity to help combat the rising costs of treatment and increase patient access to biologic therapy. Attainment of regulatory approval, involving numerous nonclinical and clinical comparative studies versus each reference product, is only one of several barriers to realize the potential gains offered by biosimilars. It is important to understand the current perceptions and informational needs of different stakeholders if biosimilars are to be accepted and widely used in the clinic. We discuss these considerations and refer to recent experiences with CT-P13, a biosimilar of the TNF inhibitor infliximab used to treat rheumatoid arthritis and other inflammatory disorders.

Biosimilars are highly similar versions of approved biologic drugs that may confer equivalent efficacy at a reduced cost. Patents for several biological cancer therapeutics are past or approaching expiry, presenting an opportunity to increase affordability and global accessibility of key drugs through the development of biosimilars. To receive approval, a biosimilar must show no clinically meaningful differences from the reference product in terms of efficacy or safety. The first monoclonal antibody biosimilar cancer therapeutic to gain approval was CT-P10, a biosimilar of rituximab. Here, we review the oncology clinical development program for CT-P10, providing insights into the rationale for, and design of, CT-P10 clinical trials in patients with cancer. Trials of biosimilar cancer therapeutics in development are also discussed.

For a biosimilar to gain regulatory approval, a comprehensive comparability exercise must demonstrate that it is highly similar to its originator biologic, or reference product. Once biosimilarity has been shown, it is possible to approve the biosimilar for additional indications held by the reference product, without clinical trials in these indications. Extrapolation of clinical data is permitted by regulatory agencies as long as it is scientifically justified. CT-P10, a biosimilar of rituximab, was recently approved in Europe for all indications held by its reference product, incorporating both autoimmune diseases and hematological cancers. Here, we review the scientific rationale for extrapolation in biosimilar development using the example of CT-P10 as a case study.

Pexa-Vec (pexastimogene devacirpvec; JX-594) has emerged as an attractive tool in oncolytic virotherapy. Pexa-Vec demonstrates oncolytic and immunotherapeutic mechanisms of action. But the determinants of resistance to Pexa-Vec are mostly unknown. We treated hemoatologic malignant cells with Pexa-Vec and examined the gene-expression pattern of sensitive and resistant cells. Human myeloid malignant cell lines (RPMI-8226, IM-9, K562, THP-1) and lymphoid cancer cell lines (MOLT4, CCRF-CEM, Ramos, U937) were treated with Pexa-Vec. Pexa-Vec was cytotoxic on myeloid cell lines in a dose-dependent manner, and fluorescent imaging and qPCR revealed that Pexa-Vec expression was low in RAMOS than IM-9 after 24 hrs and 48 hrs of infection. Gene expression profiles between two groups were analyzed by microarray. Genes with at least 2-fold increase or decrease in their expression were identified. A total of 660 genes were up-regulated and 776 genes were down-regulated in lymphoid cancer cell lines. The up- and down-regulated genes were categorized into 319 functional gene clusters. We identified the top 10 up-regulated genes in lymphoid cells. Among them three human genes (LEF1, STAMBPL1, and SLFN11) strongly correlated with viral replication. Up-regulation of PVRIG, LPP, CECR1, Arhgef6, IRX3, IGFBP2, CD1d were related to resistant to Pexa-Vec. In conclusion, lymphoid malignant cells are resistant to Pexa-Vec and displayed up-regulated genes associated with resistance to oncolytic viral therapy. These data provide potential targets to overcome resistance, and suggest that molecular assays may be useful in selecting patients for further clinical trials with Pexa-Vec.

Background: We conducted the study to examine accuracy of the magnetoencephalography (MEG) spike source localization in presurgical evaluation of patients with medically refractory focal epilepsy., Methods: Ten consecutive patients with refractory focal epilepsy who were candidates for two-stage surgery with long-term intracranial electroencephalography (ICEEG) monitoring were enrolled. Interictal MEG recordings with simultaneous scalp EEG were obtained within 7days before the ICEEG electrode implantation. The location of each MEG spike source was quantitatively compared with ICEEG spike foci (focal area of interictal spikes) and ICEEG ictal foci (earliest cortical origin of seizures). Gyral-width concordance and sublobar concordance were also determined for all MEG spike sources. Gyral-width concordance was defined by distance of 15mm or less between MEG spike sources and ICEEG spike foci or ICEEG ictal foci., Results: Visual analyses of the MEG traces of all 10 patients revealed 292 spikes (29.2±24.0 per patient). Spike yield of the MEG was similar to the simultaneously recorded scalp EEG. MEG spike sources were closely located with ICEEG spike foci (distance: 9.3±10.8mm). Clustered MEG spike sources were even closer to ICEEG spike foci (distance: 7.3±6.4mm). MEG spike sources, even clustered ones, were less concordant with ICEEG ictal foci and had significant longer distance from ICEEG ictal foci (distance: 21.5±15.6mm for all sources, 19.7±13.7mm for clustered sources). Gyral-width concordance rate and sublobar concordance rate were also higher with ICEEG interictal spike foci than with ICEEG ictal foci. On the other hand, 53.4% of interictal spike foci from ICEEG were not detected by interictal MEG recordings., Conclusions: MEG spike sources, especially clustered ones, from interictal recording could localize the irritative zone of ICEEG with a high accuracy. However, MEG spike sources have relatively poor correlation with seizure onset zone and lower sensitivity in identifying all irritative zones of ICEEG. This limitation should be considered in the interpretation of MEG results., (Copyright © 2016. Published by Elsevier B.V.)

The insulin-like growth factor (IGF) axis plays a crucial role in proliferation, differentiation, migration, angiogenesis, and apoptosis. The present study evaluated the associations between IGF axis single-nucleotide polymorphisms (SNPs) and clinical outcomes in advanced gastric cancer (AGC) patients treated with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX). A total of 190 patients undergoing FOLFOX chemotherapy for AGC were considered eligible for this study. Forty-four SNPs of 10 IGF axis genes were genotyped. Levels of serum IGF1 were measured using enzyme-linked immunoassays. SNPs of the IGF1R (rs12423791), and IGF1 (rs2162679, rs5742612, rs35767) genes were significantly associated with tumor response to FOLFOX. SNPs of rs4619 and rs17847203 were significantly associated with PFS (hazard ratio [HR] 0.575, 95% CI 0.385-0.858, P = 0.007; and HR 2.530, 95% CI 1.289-4.966, P = 0.007; respectively). SNPs of rs2872060 were significantly associated with OS-OS was shorter in patients carrying the TT variant than in those with the GG/GT genotypes (HR, 1.708, 95% CI 1.024-2.850, P = 0.040). The GT genotype of rs12847203 was also identified as an independent prognostic factor (HR 2.087, 95% CI 1.070-4.069, P = 0.031). These results suggest that IGF axis-pathway SNPs could be used as prognostic biomarkers of the outcome of FOLFOX chemotherapy in AGC patients. This information may facilitate identification of population subgroups that could benefit from IGF1R-targeted agents., Competing Interests: The authors have no conflicts of Interest.

Purpose: To evaluate the efficacy of hydromorphone-OROS (HM-OROS) in reducing sleep disturbance and relieving cancer pain., Materials and Methods: One hundred twenty cancer patients with pain (numeric rating scale [NRS] ≥ 4) and sleep disturbance (NRS ≥ 4) were evaluated. The initial HM-OROS dosing was based on previous opioid dose (HM-OROS:oral morphine=1:5). Dose adjustment of the study drug was permitted at the investigator's discretion. Pain intensity, number of breakthrough pain episodes, and quality of sleep were evaluated., Results: A total of 120 patients received at least one dose of HM-OROS; 74 of them completed the final assessment. Compared to the previous opioids, HM-OROS reduced the average pain NRS from 5.3 to 4.1 (p < 0.01), worst pain NRS from 6.7 to 5.4 (p < 0.01), sleep disturbance NRS from 5.9 to 4.1 (p < 0.01), incidence of breakthrough pain at night from 2.63 to 1.53 times (p < 0.001), and immediate-release opioids use for the management of breakthrough pain from 0.83 to 0.39 times per night (p = 0.001). Of the 74 patients who completed the treatment, 83.7% indicated that they preferred HM-OROS to the previous medication. The adverse events (AEs) were somnolence, asthenia, constipation, dizziness, and nausea., Conclusion: HM-OROS was efficacious in reducing cancer pain and associated sleep disturbances. The AEs were manageable.

Purpose: Little is known about the clinical features of advanced gastric cancer (AGC) combined with disseminated intravascular coagulation (DIC). The main objective of this study was to determine the clinical outcome of patients with AGC complicated by DIC., Materials and Methods: We conducted a retrospective review of 68 AGC patients diagnosed with DIC at four tertiary medical centers between January 1995 and June 2010., Results: Sixty eight patients were included. The median age was 55 years (range, 25 to 78 years). Nineteen patients received chemotherapy, whereas 49 patients received only best supportive care (BSC). The median overall survival (OS) of the 68 patients was 16 days (95% confidence interval [CI], 11 to 21 days). Significantly prolonged OS was observed in the chemotherapy group, with a median survival of 61 days compared to 9 days in the BSC group (p<0.001, log-rank test). Age and previous chemotherapy were another significant factors that were associated with OS in univariate analysis. In multivariate analysis, age (≥65 vs. <65; hazard ratio [HR], 0.38; 95% CI, 0.18 to 0.78; p<0.001), chemotherapy (BSC vs. chemotherapy; HR 0.31; 95% CI, 0.15 to 0.63; p<0.001), and previous chemotherapy (yes or no; HR, 0.49; 95% CI, 0.25 to 0.98; p<0.045) were consistently independent prognostic factors that impacted OS., Conclusion: Our study showed that patients with AGC complicated by DIC had very poor OS, and suggested that chemotherapy might improve OS of these patients.

Biliary tract cancer (BTC) is a relatively uncommon type of cancer, accounting for ∼4% of the malignant neoplasms of the gastrointestinal tract. The aim of this study was to determine whether the expression of thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) predict clinical outcome in BTC patients treated with adjuvant 5-fluorouracil (5-FU)-based chemotherapy. TS and TP expression were found to be significantly correlated with cancer location (P=0.044 and 0.031, respectively). The multivariate analysis revealed that age [hazard ratio (HR)=2.157, P=0.008], stage (HR=2.234, P<0.001), resection margin status (HR=2.748, P=0.004) and TP expression (HR=2.014, P=0.039) were independently associated with overall survival (OS).

Background: Although 30-50 % of patients with brain tumors experience epileptic seizure as the presenting clinical symptom, and another 10-30 % are at risk for developing epilepsy in the later stages of the disease, the mechanisms of tumor-related epileptogenesis are poorly understood. We used magnetoencephalography (MEG) to investigate sensory evoked fields (SEFs) in patients with frontal lobe brain tumors as a means of evaluating the neuronal activity of peri-tumoral cortex., Methods: Twelve patients with frontal lobe brain tumors underwent MEG. We calculated the equivalent current dipole strength of two components of the primary sensory cortical response (N20m and P35m) and compared the P35m/N20m ratio in the tumor hemisphere vs. the normal hemisphere. There were two subsets of patients: group I, in which P35m/N20m was higher in the tumor hemisphere (n= 7), and group II, in which P35m/N20m was higher in the normal hemisphere (n=5). We looked for associations between clinical factors and P35m/N20m within each group., Results: All patients with seizure presentation were in group I, whereas only two patients without seizure presentation were in group I (Fisher exact test, p=0.028). No other clinical factors were related to P35m/N20m. The mean ratio of P35m/N20m equivalent current dipole strength in patients with seizure presentation was 4.07 ± 2.38 in the tumor hemisphere and 2.00 ± 0.55 in the normal hemisphere. This difference was statistically significant (Mann-Whitney test, p=0.030)., Conclusion: The paradoxical increase in P35m/N20m in patients with seizure presentation suggests that decreased inhibitory neuronal activity is a potential cause of tumorrelated epilepsy.

Background: Traditionally, tinnitus accompanied by hemifacial spasm has been considered a type of hyperactive neurovascular compression syndrome that is similar to hemifacial spasm alone because of the anatomically close relationship between the facial nerve and cochlear nerve as well as the hyperactive clinical nature., Methods: Participants were 29 subjects who presented with hemifacial spasm and neuroradiological evidence of vascular compression of the cranial (facial/cochlear) nerve. We used magnetoencephalography (MEG) to estimate the activity of the cochlear nerve in patients with and without tinnitus on the ipsilateral side. We compared the difference in the latency and the ratio of the equivalent current dipole (ECD) strength between the ipsilateral and contralateral sides of the spasm and tinnitus., Results: Cochlear nerve activity in patients with tinnitus was increased with a shorter latency (p = 0.016) and stronger ECD strength (p = 0.028) compared with patients without tinnitus., Conclusion: The MEG results from normal-hearing patients who had tinnitus accompanied by hemifacial spasm suggest that the hyperactivity of the auditory central nervous system may be a crucial pathophysiological factor in the generation of tinnitus in these patients. The neurovascular compression that causes sensory input from the pathologic facial nerve activity may contribute to this hyperactivity of the central auditory nervous system.

Purpose: To assess the value of screening ultrasonography (US) in the detection of nonpalpable locoregional recurrence following mastectomy for breast cancer and to describe the US appearances of occult recurrent cancers., Materials and Methods: During a 36-month period, 1180 consecutive US screenings were performed for mastectomy sites and ipsilateral axillary fossae in 468 asymptomatic women who had undergone mastectomy for breast cancer. All US results were divided into three groups: negative findings, probably benign nodules, and suspicious for malignant nodules. The final diagnoses were based on pathology results and clinical or sonographic follow-up for more than 12 months. The diagnostic performance of US for detecting nonpalpable locoregional recurrence was assessed. The US appearances of occult recurrent cancers were retrospectively reviewed., Results: Of the 468 patients assessed, 19 (4.1%) showed "suspicious for malignant nodules"; of these lesions, 10 were malignant. One false-negative case was identified. The sensitivity and specificity were 90.9% and 98.0%, respectively. A biopsy positive predictive value of 52.6% was observed. Cancer detection rates were 2.1% with US screenings of mastectomy sites and ipsilateral axillary fossae. The common US features of occult recurrences at the mastectomy sites were irregular shaped, not-circumscribed marginated, and hypoechoic masses with intratumoral vascularities. The most common location was within the deep muscle layer., Conclusion: Although locoregional recurrence infrequently occurs after mastectomy for breast cancer, screening US enables detection of nonpalpable cancer before it can be detected by clinical examination. Routine follow-up US can be advocated for early detection of nonpalpable locoregional recurrent cancer., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: The aim of this study is to evaluate the associations between vascular endothelial growth factor (VEGF) Single-nucleotide polymorphisms (SNPs) and clinical outcome in advanced gastric cancer patients treated with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX)., Methods: Genomic DNA was isolated from whole blood, and six VEGF (-2578C/A, -2489C/T, -1498 T/C, -634 G/C, +936C/T, and +1612 G/A) gene polymorphisms were analyzed by PCR. Levels of serum VEGF were measured using enzyme-linked immunoassays., Results: Patients with G/G genotype for VEGF -634 G/C gene polymorphism showed a lower response rate (22.2%) than those with G/C or C/C genotype (32.3%, 51.1%; P = 0.034). Patients with the VEGF -634 G/C polymorphism G/C + C/C genotype had a longer progression free survival (PFS) of 4.9 months, compared with the PFS of 3.5 months for those with the G/G (P = 0.043, log-rank test). By multivariate analysis, this G/G genotype of VEGF -634 G/C polymorphism was identified as an independent prognostic factor (Hazard ratio 1.497, P = 0.017)., Conclusion: Our data suggest that G/G genotype of VEGF -634 G/C polymorphism is related to the higher serum levels of VEGF, and poor clinical outcome in advanced gastric cancer patients.

Background: Gemcitabine has been recognized as a standard chemotherapy in advanced pancreas cancer(APC). We conducted a phase II study of a triple combination regimen (GPT) consisting of gemcitabine (G), cisplatin(P) and erlotinib (T) in patients with APC., Patients and Methods: Chemotherapy-naïve patients with locally advanced or metastatic, histologically confirmed adenocarcinoma of the pancreas were treated with erlotinib 100 mg daily, 1,000 mg/m2 of gemcitabine and 25 mg/m2 of cisplatin administered on days 1 and 8, respectively, every 3 weeks.The primary end point was objective response. Secondary end points included progression-free survival, overall survival and toxicity. The study was designed according to the optimal two-stage design., Results: Twenty-two patients were enrolled between June 2009 and August 2010. No complete response was achieved and partial response was observed in 5 patients (26%), Stable disease in 7 (37%), and progressive disease in 7 (37%). The median time to progression was 4.0 months (95% CI: 2.9–5.1 months), and the median overall survival 6.8 months (95% CI: 3.7–9.9 months). The response rate in stage I reached the target (≥3/22,p0010%) established for movement to stage II but this study was determined to close earlier than planned because of unexpected treatment-related deaths (3 patients)., Conclusion: The triple regimen of GPT is effective for APC. Treatment related mortalities factored early closure of this GPT protocol. Considering effect and toxicity, this triple regimen seems to offer few benefits to the patients compared with gemcitabine based doublets. (ClinicalTrials.gov number, NCT00922896).

Fascin is an actin-binding protein that provides mechanical support and cell motility, and involves cancer cell metastasis. We investigated fascin protein expression in gastric cancer and assessed their relationship with clinicopathologic parameters and survival rates. In addition, we researched galectin-3 protein expression to study fascin action mechanisms. We performed immunohistochemisty with fascin and galectin-3 antibodies in 471 gastric carcinomas, using tissue microarrays. Fascin was positive in 14.9% (70/471) of the samples, and fascin expression was related to worse survival rates (P < 0.001), high clinical stage (P < 0.001), high T stage (P < 0.001), nodal metastasis (P < 0.001), lymphovascular invasion (P= 0.001) and the intestinal type of Lauren classification (P= 0.015). Galectin-3 protein expression was positive in 83.9% (395/471) of the samples and was reversely correlated with fascin protein expression (P= 0.020). Galectin-3 expression was related to low clinical stage (P < 0.001), but not to survival rates in multivariate analysis. In multivariate analysis, fascin expression was related to worse survival rates (HR = 1.56, P= 0.036), and can be an independent poor prognostic factor in gastric cancer., (© 2012 The Authors. Pathology International © 2012 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Background: Recently, laparoscopic resection for relatively small sized gastric gastrointestinal stromal tumors (GISTs) has been widely accepted as minimally invasive surgery. However, no report on the long-term safety and efficacy of this surgery for large sized gastric GISTs has been published to date., Methods: Between July 1998 and January 2011, 104 consecutive patients who underwent resection for gastric GISTs were enrolled in this retrospective study. We assessed the clinicopathological characteristics, postoperative outcomes, patient survival, and tumor recurrence., Results: Of the 104 patients with gastric GISTs who were included in the study, there were 47 males and 57 females whose mean age was 59.8 years. Sixty-four patients (61.5%) had symptoms associated with tumor. Ten patients included in the group 1, 49 in the group 2, 15 in the group 3a, 9 in the group 5, 14 in the group 6a, and 7 in the group 6b. There was one minor complication and no mortalities. Recurrence was noted in 5 patients, with a median follow-up period of 49.3 months (range, 8.4 to 164.4). The 5-year overall and disease free survival rates of 104 patients were 98.6% and 94.8%, respectively. When comparing large tumor (5-10 cm) between laparoscopic and open surgery, there were statistically differences in age, tumor size, tumor location, and length of hospitalization. There were no statistical differences in the 5-year survival rate between laparoscopic and open surgery for large tumor (5-10cm)., Conclusion: Laparoscopic surgery is feasible and effective as an oncologic treatment of gastric GISTs. Moreover, laparoscopic surgery can be an acceptable alternative to open methods for gastric GISTs of size bigger than 5 cm.

Aim: To assess the prognostic significance of nuclear factor-κB (NF-κB) and its target genes in gastric cancer., Methods: The tumor tissues of 115 patients with gastric cancer were immunohistochemically evaluated using monoclonal antibodies against NF-κB RelA. Preoperative serum levels of vascular endothelial growth factor (VEGF), interleukin-6 (IL-6) were assessed via enzyme-linked immuno-sorbent assay. C-reactive protein (CRP) and serum amyloid A (SAA) were measured via immunotrubidimetry., Results: Positive rate of NF-κB RelA was 42.6%. NF-κB RelA expression in tumor tissues was also related to serum levels of IL-6 (P = 0.044) and CRP (P = 0.010). IL-6, SAA, CRP were related to depth of invasion, VEGF and SAA were correlated with lymph node metastasis. IL-6, VEGF, SAA and CRP were related to the stage. Univariate analysis demonstrated that immunostaining of NF-κB RelA, levels of IL-6, VEGF, SAA were significantly related with both disease free survival and overall survival (OS). Multivariate analysis verified that NF-κB RelA [hazard ratio (HR): 3.40, P = 0.024] and SAA (HR: 3.39, P = 0.045) were independently associated with OS., Conclusion: Increased expression of NF-κB RelA and high levels of serum SAA were associated with poor OS in gastric cancer patients.

Background: Myelodysplastic syndrome (MDS) is a preleukemic condition that transforms into acute myeloid leukemia. However, the genetic events underlying this transformation remain poorly understood. Aberrant DNA methylation may play a causative role in the disease and its prognosis. Thus, we compared the DNA methylation profiles in refractory anemia with excess blast (RAEB) to those in refractory cytopenia with multilineage dysplasia (RCMD)., Methods: Bone marrow samples were collected from 20 patients with primary MDS (9 with RAEB and 11 with RCMD), and peripheral blood samples were collected from 4 healthy controls. These samples were assessed using a commercial whole genome-wide methylation assay. Methylation-specific polymerase chain reaction (PCR) was used to detect the methylation of candidate gene promoters in RAEB and RCMD., Results: Microarray data revealed significant hypermethylation in 69 genes within RAEB but not RCMD. Candidate genes were mapped to 5 different networks, and network 1 had the highest score due to its involvement in gene expression, cancer, and cell cycle. Five genes (GSTM5, BIK, CENPH, RERG, and ANGPTL2) were associated with malignant disease progression. Among them, the methylated promoter pairs of GSTM5 (55.5% and 20%), BIK (20% and 0%), and ANGPTL2 (44.4% and 10%) were observed more frequently in RAEB., Conclusion: DNA methylation of GSTM5, BIK, and ANGPTL2 may induce epigenetic silencing and contribute to the increasing blasts and resulting MDS progression; however, the functions of these genes were not determined. Further study focusing on epigenetic silencing using various detection modalities is required.

Purpose: Natural orifice transluminal endoscopic surgery (NOTES) is a new method of accessing intracavitary organs in order to minimize pain by avoiding incisions in the body wall. The aim of this study is to determine patients' acceptance of NOTES in Korea and to compare their views about laparoscopic surgery and NOTES for benign and malignant diseases., Materials and Methods: The target number of total subjects was calculated to be 540. The subjects were classified into 18 sub-groups based on age groups, gender, and history of prior surgery. The questionnaire elicited information about demographic characteristics, medical check-ups, diseases, endoscopic and surgical histories, marital status and childbirth, the acceptance of NOTES, and the preferred routes for NOTES. In addition, the subjects chose laparoscopic surgery or NOTES for a hypothetical cholecystectomy and rectal cancer surgery, and responded to questions regarding the acceptable complication rate of NOTES, the appropriate cost of NOTES, and the reason(s) why they did not select NOTES., Results: 486 of 540 patients (90.0%) who agreed to participate in this study completed the questionnaire. NOTES was preferred by the following patients: elderly; a history of treatment due to a disease; having regular check-ups; and a history of an endoscopic procedure (p<0.05). The most preferred route for NOTES was the stomach (67.1%). Eighty-four percent of the patients choosing NOTES responded that the complication rate of the new surgical method should be the same or lower than laparoscopic surgery. Vague anxiety over a new surgical method was the most common reason why NOTES was not selected in benign and malignant diseases (64% and 73%), respectively., Conclusion: Patients appear to be interested in the potential benefits of NOTES and would embrace it if their concerns about safety are met. We believe that qualified surgical endoscopists can meet these safety concerns, and that NOTES development has the potential to flourish.

Background: The criteria by Camitta for diagnosis in severe aplastic anemia (SAA) has been used since 1976. However, there has been no attempt to verify the Camitta's criteria, that the survival in patients with SAA may differ by absolute neutrophil count (ANC), platelet count (PLT), and corrected reticulocyte count (CRC), which are components of the Camitta's criteria., Methods: 117 SAA patients diagnosed by the Camitta's criteria were analyzed, retrospectively. Univariate and multivariate analyses were used to evaluate the factors affecting overall survival (OS)., Results: Response by immunosuppressive therapy (IST) or stem cell transplantation (SCT) significantly affected OS (P=0.001). Therefore, we excluded treatment responders for analysis. Finally, 92 SAA patients including treatment non-responders by IST or SCT and conservative care group were analyzed by using univariate and multivariate analyses. The median age of analyzed patients was 54.5 years. Male to female ratio was 1:1. The median follow-up duration was 74.23 months (range, 54.71-93.74 months). The median ANC, PLT, and CRC were 394/µL, 12,000/µL, and 0.39%, respectively. In multivariate analyses, ANC <500/µL or ≥500/µL (P=0.015, HR 2.694, 95% CI: 1.20-6.01) and age (P=0.015, HR 1.022, 95% CI: 1.00-1.04) were the significant factors for OS., Conclusion: ANC could be an essential, not an optional criterion for diagnosing SAA. This study suggests the possibility that the Camitta's criteria be modified. Studies in large cohorts are needed to transform the Camitta's criteria.

Background: This study was conducted to clarify the frequency of the BRAF mutation in primary melanomas and its correlation with clinicopathologic parameters., Methods: We analyzed the frequency of BRAF mutation in patients with primary cutaneous melanoma (n=58) or non-cutaneous one (n=27) by performing dual priming oligonucleotide-based multiplex real-time polymerase chain reaction to isolate and to purify the DNA from the formalin-fixed and paraffin-embedded tumors., Results: The BRAF mutation was found in 17.2% (10/58) of patients with primary cutaneous melanoma and 11.1% (3/27) of those with non-cutaneous melanoma. The frequency of BRAF mutation was not correlated with any clinicopathologic parameters with the exception of the patient age. The frequency of the BRAF mutation was significantly higher in patients younger than 60 years as compared with those older than 60 years (p=0.005)., Conclusions: Compared with previous reports, our results showed that the frequency of the BRAF mutation was relatively lower in patients with primary cutaneous melanoma. Besides, our results also showed that the frequency of the BRAF mutation had an inverse correlation with the age. Further studies are warranted to exclude methodological bias, to elucidate the difference in the frequency of the BRAF mutation from the previous reports from a Caucasian population and to provide an improved understanding of the molecular pathogenesis of malignant melanoma.

Purpose: When designing this trial, there was no evidence that salvage chemotherapy (SLC) in advanced gastric cancer (AGC) resulted in substantial prolongation of survival when compared with best supportive care (BSC). However, SLC is often offered to pretreated patients with AGC for anecdotal reasons., Patients and Methods: Patients with AGC with one or two prior chemotherapy regimens involving both fluoropyrimidines and platinum and with an Eastern Cooperative Oncology Group performance status (PS) 0 or 1 were randomly assigned in a ratio of 2:1 to SLC plus BSC or BSC alone. Choice of SLC-either docetaxel 60 mg/m(2) every 3 weeks or irinotecan 150 mg/m(2) every 2 weeks-was left to the discretion of investigators. Primary end point was overall survival (OS)., Results: Median OS was 5.3 months among 133 patients in the SLC arm and 3.8 months among 69 patients in the BSC arm (hazard ratio, 0.657; 95% CI, 0.485 to 0.891; one-sided P = .007). OS benefit for SLC was consistent in most of the prospectively defined subgroups, including age, PS, number of prior treatments, metastatic sites, hemoglobin levels, and response to prior chemotherapy. SLC was generally well tolerated, and adverse events were similar in the SLC and BSC arms. We found no median OS difference between docetaxel and irinotecan (5.2 v 6.5 months; P = .116)., Conclusion: To our knowledge, this is the largest phase III trial comparing SLC plus BSC with BSC alone in AGC. In pretreated patients, SLC is tolerated and significantly improves OS when added to BSC.

The objective of this study was to clarify whether the neutrophil-lymphocyte ratio (NLR) and the platelet-lymphocyte ratio (PLR) are significant prognostic markers in patients with resectable colorectal cancer (CRC). A total of 200 patients who underwent curative resection for CRC were enrolled. The NLR and PLR were positively correlated (p < 0.001). Both the NLR and PLR were shown to be good prognostic biomarkers of overall survival (OS) (p=0.002 and p=0.001, respectively). The PLR was an independent prognostic factor of OS based on multivariate analysis (hazard ratio, 1.971; 95% confidence interval, 1.102-3.335; p=0.021).

Purpose: To assess the efficacy of imatinib for different tumor genotypes in Korean patients with advanced gastrointestinal stromal tumors (GIST)., Material and Methods: Clinical data were collected from 370 consecutive patients with locally advanced unresectable, metastatic, or recurrent GIST treated with imatinib 400 mg/day between August 2001 and December 2007 at 20 Korean institutions. Tumor genotypes were determined for 290 patients by direct DNA sequencing of KIT exons 9, 11, 13, and 17, and PDGFRA exons 12, 14, and 18., Results: Of 290 patients assessed for genotype, 261 (90.0%) had mutations in KIT: 222 (76.6%) in exon 11, 35 (12.1%) in exon 9 and two each (0.7%) for exons 13 and 17. Four patients (1.4%) had mutations in the PDGFRA gene: one in exon 12, and three in exon 18. Twenty-five patients (8.6%) had no detectable mutations. The best responses of the 235 patients with measurable lesions were: 15 complete response (6.4%), 126 partial response (53.5%), 86 stable disease (36.6%), and eight progressive disease (3.4%). Patients with KIT exon 9 mutations, compared with patients with KIT exon 11 mutations, had a lower objective response rate (36.7% vs. 63.6%, p = 0.007) and a shorter progression-free survival (median 28.7 months vs. 49.4 months, p = 0.001). No statistical difference in overall survival was observed between these genotypes., Conclusion: This study confirms that imatinib efficacy is dependent on genotype in Korean GIST patients, consistent with results demonstrated by Western patients with GIST.

Aim: To determine the efficacy of bevacizumab in patients with metastatic colorectal cancer (MCRC) who have failed prior chemotherapy without bevacizumab., Methods: Between March 2002 and June 2010, 40 patients in South Korea with MCRC who were treated with bevacizumab plus chemotherapy as a second or later-line treatment were analyzed retrospectively for their overall response rate (ORR), overall survival (OS), and progression-free survival (PFS). The tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors guidelines., Results: All of the patients had progressed under prior chemotherapy without bevacizumab. Three patients (7.5%) exhibited an ORR, twenty one patients (52.5%) exhibited stable disease (SD), and fifteen patients (37.5%) exhibited disease progression. The median duration of the OS and PFS were 14.0 mo and 6.13 mo respectively. The median OSs were 16.60, 14.07 and 13.00 mo for second-line, third-line and fourth- or later-line treatments, respectively. The median PFSs were 7.23, 7.30 and 3.87 mo for the second-line, third-line and fourth- or later-line treatments, respectively., Conclusion: In patients with MCRC, bevacizumab combined chemotherapy may be beneficial during second- or later-line treatment.

Background: Hemifacial spasm patients often suffer from non-motor symptoms such as tinnitus. These non-motor symptoms are known to be associated with changes in cortical activity. Magnetoencephalography (MEG) is a technique that can record brain activity noninvasively. To determine the usefulness of MEG in assessing changes in cortical activity associated with non-motor hearing symptoms in hemifacial spasm patients., Methods: We used MEG to evaluate the reactivity of the auditory cortex in 26 hemifacial spasm patients. We divided patients into a subjective tinnitus group (n = 10) and a non-tinnitus group (n = 16). The latency and amplitude of the most prominent deflection, N100m, was compared between the two groups., Results: There was a significant difference in the pure tone audiogram on the spasm side compared with the non-spasm side. After stimulation on the spasm side, the amplitude of the N100m peak in the contralateral hemisphere was lower in the subjective tinnitus group than in the non-tinnitus group., Conclusions: Our results indicate that MEG can detect differences in cortical activity between hemifacial spasm patients with and without tinnitus. This suggests that MEG can identify changes in cortical activity associated with non-motor symptoms.

Background: Palliative chemotherapy has been shown to have a survival benefit for patients with recurrent or metastatic gastric cancer. 5-fluorouracil (5-FU) and cisplatin have been widely used in a variety of combinations. We conducted a phase II study of combination chemotherapy with new agents, S-1 and oxaliplatin (SOx), in advanced gastric cancer patients in an effort to evaluate the efficacy and toxicity of this regimen., Method: Histologically confirmed recurrent or metastatic gastric cancer were treated by the oral administration of S-1 80 mg/m(2)/day on days 1-28, and oxaliplatin 85 mg/m(2) administered as a 90-min intravenous infusion on days 1, 15, and 29. Treatment courses were repeated every 6 weeks. Patients received a maximum of four cycles., Results: From Feb 2006 to May 2008, 41 patients were enrolled in this study. The ratio of males to females was 28 to 13. The median patient age was 61 years (range, 36-74 years), and 85.4% (35/41) of the patients had a performance status (ECOG) of 1. The median number of chemotherapy cycles administered was 3 (range, 1-4). According to the results of our Intent-to-Treat analysis, 22 patients (53.7%) achieved a partial response (95% CI, 38-70%). 15 patients (36.6%) evidenced a stable disease, and 1 patient (2.4%) progressed during the course of the treatment. 3 patients were lost to follow-up prior to evaluation. The median time to progression and overall survival time were 4.6 months (95% CI, 3.4-5.8 months) and 7.8 months (95% CI, 6.9-8.7 months) from the start of the chemotherapy, respectively. A total of 114 cycles were assessed for toxicity. The major hematologic toxicities included grade 2 anemia (41.2%), grade 1-2 neutropenia (28.1%), and grade 1 thrombocytopenia (23.7%). Only 1 cycle of neutropenic fever occurred. The non-hematological toxicities observed were grade 3 vomiting (12.2%) and grade 3 diarrhea (4.9%). No treatment-related deaths occurred in our patient population during the study period., Conclusion: The SOx regimen evidenced a relatively high response rate and was well tolerated as a first-line therapy for advanced gastric cancer.

Background: Tumor vascular endothelial growth factor (VEGF) is a key angiogenic factor and may have an impact on tumor progression and response to chemotherapy. The insulin-like growth factor (IGF) system is related to cell proliferation and tumor growth. However, there is limited available data regarding the clinical and prognostic significance of VEGF or IGF-1 in advanced gastric cancer. The aim of this study was to evaluate the prognostic significance of serum VEGF and IGF-1 levels in advanced gastric cancer patients who were treated with oxaliplatin/5-fluorouracil (FOLFOX)., Methods: The study population consisted of 100 advanced gastric cancer patients (median age 56 years). Patients were treated with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1 plus leucovorin 20 mg/m(2) over 10 min, followed by a 5-fluorouracil (5-FU) bolus 400 mg/m(2) and 22 h of continuous infusion of 600 mg/m(2) on days 1-2. Treatment was repeated in 2-week intervals. The levels of serum VEGF and IGF-1 were measured using enzyme-linked immunoassays., Results: There was a significant correlation between the serum level of VEGF and Lauren's classification (p = 0.030) and previous operations (p = 0.010). IGF-1 was associated with the number of metastases (p = 0.012). The median level of serum VEGF was decreased after FOLFOX chemotherapy (p = 0.034). However, none of the measured serum markers were significantly correlated with response. In univariate analysis, overall survival (p < 0.001) was significantly shorter in patients with high serum levels of VEGF. Multivariate analysis revealed that VEGF was an independent factor for overall survival (HR 2.221; 95% CI 1.377-3.583, p = 0.001). Furthermore, IGF-1 had no significant influence on the clinical outcome., Conclusion: A high level of serum VEGF is an independent prognostic factor in patients with advanced gastric cancer treated with chemotherapy. This may help to identify the patients who are more sensitive to the FOLFOX regimen., (Copyright © 2013 S. Karger AG, Basel.)

Background: The aim of this study was to investigate the surgical and oncologic outcomes of laparoscopy-assisted gastrectomy (LAG) and open gastrectomy (OG) for advanced gastric cancer (AGC) using the case-control method with a sufficient follow-up period., Patients and Methods: The authors retrospectively analyzed 89 patients who underwent LAG and 345 patients who underwent OG for AGC between August 1999 and June 2007. A total of 176 matched cases were included in the final analysis., Results: Except for tumor size and reconstruction, there were no statistically significant differences in the clinicopathological parameters between the two groups. Although operation time was significantly longer for LAG than OG (228.3 vs. 183.6 min, p < 0.0001), first flatus time and postoperative hospital stay without complications were significantly shorter in the LAG group (3.2 vs. 3.7 days, p < 0.0001; 7.0 vs. 10.4 days, p < 0.0001, respectively). Operation-related complications occurred in 7 cases (8.0%) in both groups. 13 patients (14.8%) in the LAG group and 15 patients (17.1%) in the OG group had recurrence. There was no statistically significant difference in the 5-year and disease-free survival rates between LAG and OG., Conclusions: LAG for AGC might be considered to be a minimally invasive surgery in some selected cases, although a well-designed prospective study comparing LAG with OG for AGC is needed., (Copyright © 2012 S. Karger AG, Basel.)

Purpose: Peritoneal carcinomatosis (PC) of colorectal cancer (CRC) is common and is the second most common cause of death. Clinical studies regarding chemotherapy for CRC with PC have been classically rather limited in scope. We evaluated the efficacy of modified oxaliplatin, leucovorin, and fluorouracil (m-FOLFOX4) regimen for PC of CRC origin., Materials and Methods: CRC patients with PC were treated with cycles of oxaliplatin at 85 mg/m(2) on day 1, leucovorin 20 mg/m(2) followed by 5-fluorouracil (5-FU) via a 400 mg/m(2) bolus and a 22 hours continuous infusion of 600 mg/m(2) 5-FU on days 1-2 at 2-week intervals., Results: Forty patients participated in this study. Median age was 55 years. Thirty-two patients (80.0%) received previous operation, and 60.0% of PC occurred synchronously. Thirty-five patients (87.5%) were assessable and exhibited measurable lesions. Two patients (5.7%) demonstrated complete response and five patients (14.3%) showed partial response. The median time to progression was 4.4 months (95% confidence interval, 2.5 to 6.3 months), the median overall survival time was 21.5 months (95% confidence interval, 17.2 to 25.7 months). There was no treatment related death. Presence of liver metastasis (p=0.022), performance status (p=0.039), and carcinoembryonic antigen level (p=0.016) were related to the time to progression. Patients with low carcinoembryonic antigen level (37.2 months vs. 15.6 months, p=0.001) or good performance status (22.5 months vs. 6.8 months, p=0.040) showed better overall survival., Conclusion: The m-FOLFOX4 regimen was determined to be effective for CRC patients with PC.

To determine the efficacy and tolerance of irinotecan in combination with S-1 (IRIS) for patients whose disease progressed after treatment with an oxaliplatin-based therapy for colorectal cancer (CRC). Each patient's disease had progressed after the administration of a regimen containing oxaliplatin and 5-FU. S-1 was administered orally at a fixed dose of 40 mg/m(2) twice daily on days 1-14 and 21-35. Irinotecan (150 mg/m(2)) was administered via intravenous infusion on days 1, 15, and 29. Courses were repeated every 6 weeks. 20 patients were enrolled in this study between April 2006 and March 2008. The median age was 63 years (range: 34-74), and the dominant metastasis sites were the liver, lung, and lymph nodes. The objective response rate was 20%; 1 patient registered complete response and 3 patients registered partial responses; 7 patients were stabilized (35%); and 9 evidenced progression of disease (45%). Median progression-free survival was 3.0 months (95% CI, 2.1-3.9 months) and median overall survival was 9.8 months (95% CI, 6.3-13.3 months). For the 41 cycles analyzed, the most commonly detected hematologic toxicity was grade I-II anemia (63.4%). Leukopenia occurred in 18 cycles (41.5%), including eight cycles (19.5%) of grade 3-4 leukopenia. Frequently observed non-hematologic toxicities included the following: grade I vomiting was reported in 4 patients (20%), grade 2 neuropathy occurred in 3 patients (15%), and grade 2 mucositis was noted in 2 patients (10%). Two patients died from sepsis and hematemesis during treatment. Although the response rate in stage I reached the target (≥ 3/18, p0 = 10%) established for movement to stage II, this study had to be discontinued because two patients died during treatment. Additionally, the follow-up loss rate was higher (16.6%) than we had anticipated (<10%). Even though a regime consisting of irinotecan combined with S-1 (IRIS) has proven effective in oxaliplatin-pretreated patients with advanced CRC, treatment-related mortalities and the high follow-up loss rate suggested that this IRIS protocol should result in early closure and modification.

Aim: We conducted this phase II study in an effort to evaluate the efficacy and safety of a gemcitabine single chemotherapy as a second-line treatment for biliary tract cancer (BTC) patients who evidenced disease progression after the administration of 5-fluorouracil (5-FU)-based palliative chemotherapy., Patients and Method: Patients treated previously with 5-FU-based palliative treatment as a BTC were enrolled in this study. Treatment consisted of gemcitabine at a dosage of 1,250 mg/m(2) administered intravenously over a 30-minute period on days 1 and 8 of each 21-day cycle until progression., Results: Between Feb. 2006 and July 2009, a total of 32 patients were assigned to treatment groups. 16 patients (50%) had cancers of intra-hepatic cholangiocarcinoma, 12 patients (37.5%) had gall bladder cancer, and 4 patients (12.5%) had extra-hepatic cholangiocarcinoma. In the 29 patients whose tumor responses were evaluated, two achieved a partial response, with an overall response rate of 6.9% (95% confidence interval [CI]: 0.0-16.7%). Six patients (20.7%) evidenced stable disease and 21 patients (72.4%) evidenced progression during the course of treatment. The median follow-up duration was 23.2 months (range: 3.0-53.1 months). The median time to progression (TTP) was 1.6 months (95% CI: 1.3-1.9 months), and the median overall survival (OS) time was 4.1 months (95% CI: 2.7-5.5 months). Poor performance status (ECOG 2) in patients was predictive of shorter TTP. Lower albumin levels (<3.5 g/dL) in patients were predictive of shorter TTP and OS., Conclusions: Despite first salvage chemotherapy in the phase II study for patients with 5-FU refractory BTC, the results in terms of RR, TTP, and OS were lower than expected. However, selected patients with good performance status and sufficient albumin levels may have derived some survival benefits from salvage chemotherapy.

Objective: Endoscopic resection is commonly used for early gastric cancer (EGC) in Korea and Japan. There are only a few reports of metachronous cancer after endoscopic resection. The aim of this study was to identify clinical factors associated with metachronous gastric cancer after endoscopic resection., Methods: A total of 176 patients with EGC who had underwent endoscopic submucosal dissection (ESD) were periodically followed-up with endoscopic examinations from January 2004 to December 2007. The incidence and variable factors of metachronous gastric cancer were investigated in a retrospective study., Results: The median interval between the diagnosis of primary cancer and the diagnosis of the first metachronous cancer was 30 months (range 18-42 months). Metachronous gastric cancer had developed in nine patients (5.1%) during follow-up period and seven patients (4.0%) had synchronous gastric cancer lesions within 1 year of the initial endoscopic treatment. Annual incidence rate of metachronous cancer was approximately 3.3%. Antrum atrophy and old age were significantly associated with the incidence of metachronous cancer. The status of Helicobacter pylori, size, location and gross finding of lesion had no significant relationship with metachronous occurrence., Conclusions: We should examine more carefully older patients who have atrophic gastritis because secondary cancer including metachronous cancer might occur in remnant stomach after initial successful endoscopic resection. And prospective study will be needed for the optimal endoscopic surveillance interval.

Purpose: The role of first-line trastuzumab-based therapy has been firmly established in patients with human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer. In this trial, we evaluated the efficacy and safety of a vinorelbine and trastuzumab combination chemotherapy in patients who were pretreated with anthracyclines and taxanes., Methods: Thirty-three patients with HER2 overexpressing metastatic breast cancer, all of whom had previously been treated with anthracyclines and taxanes, were included in this study. The patients were treated with 25 mg/m(2) of vinorelbine (over a 15-minute infusion) on days 1 and 8 every 3 weeks. Additionally, trastuzumab was administered at an initial dose of 4 mg/kg over 90 minutes, and was subsequently administered at weekly doses of 2 mg/kg (over 30 minutes)., Results: The median age of the patients was 53 years (range, 39-72 years). The overall response rate was 30.3% (10 patients; 95% confidence interval [CI], 23-57%). The median time to progression was 6.8 months (95% CI, 5.3-8.2 months). The median overall survival was 12.4 months (95% CI, 10.3-14.6 months). In the 194 cycles of treatment, the incidence rates of grade ≥3 neutropenia and anemia were 7.2% and 1.0%, respectively. Neutropenic fever was detected in three cycles (1.5%). The non-hematological toxicities were not severe: grade 1 or 2 nausea or vomiting was detected in 15.2%, and grade 2 neuropathy was noted in 6.1% of patients. None of the patients experienced any serious cardiac toxicity, and no treatment-related deaths occurred., Conclusion: These results show that a combination chemotherapy consisting of vinorelbine and trastuzumab is useful in patients with HER2-overexpressing metastatic breast cancer who were pretreated with anthracyclines and taxanes, with a favorable toxicity profile.

Purpose: To assess the usefulness of adenosine triphosphate-based chemotherapy response assay (ATP-CRA) results in advanced gastric cancer patients receiving adjuvant chemotherapy., Materials and Methods: Sixty-two patients underwent curative surgical resection between January, 2006 and December, 2008. Their highly purified surgical specimens were evaluated by ATP-CRAs. Of the 62, 49 had successful assay results and they received either oral 5-fluorouracil or other chemotherapies. We retrospectively analyzed data for 24 patients who were treated with oral 5-fluorouracil and whose assays were successful., Results: The median observation time was 24.6 months (range, 10.1 to 40.9 months). The median treatment time was 11.2 months (range, 1.2 to 17.7 months). The median age was 66 years (range, 30 to 81 years). Patients were grouped into sensitive- and resistant-groups according to adenosine triphosphate-based chemotherapy response results for fluorouracil. The sensitive-group showed a significantly longer time to relapse (not reached in the sensitive-group vs. 24.8 months in the resistant-group, p=0.043) and longer overall survival compared to the resistant-group (not reached in the sensitive-group vs. 35.7 months in the resistant-group, p=0.16, statistically insignificant)., Conclusion: Patients who receive curative surgical resection significantly benefit from sensitive adjuvant chemotherapy according to ATP-CRA results for time to relapse.

Purpose: The aim of this study was to evaluate the prognostic significance of the ratio between metastatic and examined lymph nodes (LNs) in patients with stage III rectal cancer., Methods: A review was made of 175 (male, 98) patients with stage III rectal cancer of R0 resection. LN disease was stratified both by the American Joint Committee on Cancer/International Union Against Cancer nodal classification (pN) and by quartiles of the lymph node ratio (LNR). Disease-free survivals (DFS) were made using Kaplan-Meier curves and assessed by the log rank test and multivariate analysis was performed using the Cox proportional hazards model., Results: Patients ranged in age from 29 to 83 (median, 60) years with median follow-up of 47 months (range, 13 to 181 months). months. There was a significant correlation between the number of metastatic LNs and the LNR (r = 0.8681, P < 0.0001). Cut-off points of LNR quartiles best to separate patients with regard to 5-year DFS were between quartile 2 and 3, and between 3 and 4 (LNR1, 2, and 3); the 5-year DFS according to such stratification was 89.6%, 55.8%, and 18.2% in LNR1, 2, and 3, respectively (P < 0.0001). Cox model identified the LNR as the most significant independent prognostic covariate; LNR2 showed 3.6 times (95% confidence interval [CI], 1.682 to 7.584; P = 0.0009) and LNR3, 18.7 times (95% CI, 6.872 to 50.664; P < 0.0001) more risky than LNR1., Conclusion: This study suggests that ratio-based LN staging, which reflects the number of LNs examined and the quality of LN dissection, is a simple and reliable system for prognostic LN stratification in patients with stage III rectal cancer.

Adenocarcinomas are a very heterogeneous subgroup of lung cancers, in which oncogenesis is linked to different molecular events. Recent evidence suggests that the hormonal status may contribute to the pathogenesis of lung adenocarcinoma. TRAP220 is the main subunit of the TRAP/Mediator complex and it binds to nuclear hormone receptors in the presence of their cognate ligand, as a cofactor of the transcription machinery. Since TRAP220 is an essential coactivator that interacts directly with estrogen receptor β (ERβ), we examined the expression of TRAP220 protein to investigate its role in lung adenocarcinoma, with particular attention being paid to its different histologic subtypes and the ERβ expression. We performed immunohistochemical detection of TRAP220 and ERβ protein in eighty-seven tissue samples from lung adenocarcinoma patients by using a tissue microarray, and Western blotting was then done to confirm the immunohistochemical observations. TRAP220 immunoreactivity was observed in 27 (31.0%) of the 87 adenocarcinoma cases. Analysis of the TRAP220 expression by Western blotting confirmed the immunohistochemical results. The TRAP220 expression was more frequently positive in the non-solid subtypes (bronchioloalveolar, acinar, and papillary patterns) than that in the solid subtype (P=0.027) and the TRAP220 expression was more frequently positive in the well-differentiated adenocarcinomas than that in the moderately or poorly differentiated adenocarcinomas (P=0.005). The tumors with a negative TRAP220 expression were larger in size (P=0.048) and they more frequently showed lymph node metastasis (P=0.002), pleural invasion (P=0.026) and an advanced TNM stage (P=0.012). The frequency of the TRAP220 expression in the cases with an ERβ expression was significantly higher than that in those cases without an ERβ expression (P=0.003). The Kaplan-Meier survival curves demonstrated that the patients with a positive TRAP220 expression had a significantly longer survival time than those patients with a negative TRAP220 expression (P=0.014). The multivariate analysis revealed that a TRAP220 expression was an independent good prognostic factor (P=0.049). Our data may be useful to understand the different biologic basis for the development and progression of the subtypes of lung adenocarcinoma., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The objective of this study was to determine whether the expressions of the excision cross-complementing (ERCC1), thymidylate synthase (TS) and glutathione S-transferase P1 (GSTP1) are predictive of clinical outcomes in advanced gastric cancer (AGC) patients receiving treatment with adjuvant 5-fluorouracil (5-FU) and cisplatin (FP) chemotherapy. One hundred forty nine patients were included in this study. ERCC1 and GSTP1 expression was correlated significantly with tumor size (p = 0.040, p = 0.018, respectively). Stage and positive lymph node ratio were associated independently with disease free survival (DFS) and overall survival (OS). Both ERCC1 and GSTP1 expression had a significant impact on OS (hazard ratio = 0.069, p = 0.021). TS expression was not related to DFS and OS.

Introduction and Hypothesis: Single-nucleotide polymorphisms (SNPs) and haplotypes in the x-ray repair cross-complementing group 1 (XRCC1) gene, which is one of the base excision repair genes, are thought to be associated with the risk of non-small cell lung cancer (NSCLC)., Methods: We genotyped three coding (Arg280His, Arg399Gln, and Gln632Gln) SNPs and six haplotype-tagging SNPs (htSNPs) for 140 advanced NSCLC cases and 217 healthy controls (all Koreans) using unconditional logistic regression analysis, and this was adjusted for age, gender, and the smoking status. The haplotypes were reconstructed according to the genotyping data and the linkage disequilibrium status of these nine SNPs., Results: The minor allele heterozygotes of the rs1001581 htSNP showed an increased risk of NSCLC (adjusted odds ratio = 2.118, p = 0.013), and the minor allele homozygotes of the rs2293036 htSNP showed a decreased risk of NSCLC (adjusted odds ratio = 0.363, p = 0.020). Seven possible haplotypes were demonstrated in this study (haplotype frequency >1%). The GGGGGGGGG haplotype, which is composed of nine major alleles, showed a protective effect for developing NSCLC (odds ratio = 0.433, p = 0.002); however, the GGGGGGAGG haplotype that contained the minor allele of the rs1001581 demonstrated an increased risk of NSCLC (odds ratio = 1.597, p = 0.044). The above associations were similarly noted for the never smokers, and so the smoking status might modify the associations between the x-ray repair cross-complementing group 1 (XRCC1) genetic variants and the risk of developing NSCLC. On 10-million permutation testing, only the GGGGGGGGG haplotype was significantly associated with a decreased risk of NSCLC in the total group (p = 0.001)., Conclusions: This study presents several novel aspects of the genetic susceptibility to develop NSCLC. Larger studies that will focus on the role of the rs1001581 and rs2293036 htSNPs and haplotypes for developing NSCLC are needed in the future.

Background: The aim of this study was to improve the predictive power of the WHO classification-based prognostic scoring system (WPSS) by including age in patients with the myelodysplastic syndrome (MDS)., Patients and Methods: 136 Korean patients with de novo MDS between 1995 and 2008 were evaluated retrospectively. All patients were reclassified according to WHO criteria. 114 patients were included in the final analysis. An individualized age-adapted scoring system was developed to improve the accuracy of prognosis of the WPSS., Results: The WPSS was significantly associated with the prediction of survival and the leukemia-free survival. While the risk of a patient with the WPSS was best represented by the values 0 (very low), +1 (low), +2 (intermediate), +3 (high), and +4 (very high), these values were found to vary between -1.0 and 4.2 in the same patients when age was included as a factor. The WPSS may vary according to age, <55 or ≥55 years. The estimated difference in median survival was more prominent in the lower risk groups of the WPSS than in the higher-risk groups., Conclusion: In addition to the WPSS, age was found to significantly influence the prognosis of patients with MDS and provided a more individualized prognosis for the patients with MDS., (Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.)

Background: Cytogenetic abnormalities (CAs) have been reported frequently in patients with otherwise typical aplastic anemia (AA), but their implications in the prognosis and in the evolution to hematologic malignancies are controversial., Methods: We retrospectively analyzed 127 adult AA patients who had successful cytogenetic analysis at initial diagnosis., Results: The patients were classified into 3 groups according to the initial and follow-up results of cytogenetic profiles. Group 1 included patients who had persistent AA with normal cytogenetic profiles (N=117); Group 2, those who had a normal cytogenetic profile at initial diagnosis but later acquired CA (N=4, 3.1%); and Group 3, those who had CA at the initial diagnosis, regardless of follow-up cytogenetic status (N=6,4.7%). In Group 2, 2 patients later developed CA without progression to acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS); the other 2 patients later progressed to AML. None of the patients in Group 3 progressed to AML or MDS. There was no significant difference in overall survival between Groups 1 and 3., Conclusion: AA patients with CA at initial diagnosis or follow-up may not be at greater risk for evolution to AML or MDS, or show shorter survival periods. Prospective studies and a larger patient samples are needed to establish the clinical relevance of CA.

Aim: Adjuvant chemoradiation has become a standard of care in the USA. We evaluated the efficacy and toxicity of adjuvant chemoradiation versus chemotherapy in completely resected locally advanced gastric cancer., Methods: Patients with stage IIIA, IIIB and IV (without metastasis) gastric cancer were treated with chemoradiation and 5-fluorouracil/cisplatin (FP) (arm A) or FP (arm B). Arm A consisted of one cycle of FP followed by 4500 cGY to radiation field with capecitabine. One month after completion of radiotherapy, patients received three additional cycles of FP every 3 weeks. Arm B consisted of six cycles of FP., Results: A total of 61 patients were enrolled, of whom 31 were placed in arm A and 30 in arm B. The median follow-up duration was 77.2 months (range 24-92.8 months). We did not find any difference in 3-year disease-free survival between arm A and B (80.0 vs 75.2%, respectively; P = 0.887). There was no significant difference between the arms in 5-year disease-free survival (76.7 vs 59.1%, respectively; P = 0.222) or overall survival (70.1 vs 70.0%, respectively; P = 0.814). Seven patients (22.6%) relapsed in arm A and 12 patients (40%) relapsed in arm B. Grade 3/4 neutropenia occurred in 48.5% of patients in arm A and 22.9% in arm B. Grade 3 nausea or vomiting occurred in 6% in arm A and 14.6% in arm B., Conclusion:   We could not make any conclusion about the benefit of adding radiation to adjuvant chemotherapy., (© 2010 Blackwell Publishing Asia Pty Ltd.)

Background: The principal objective of this study was to evaluate the prognostic significances of p53, hypoxia inducible factor-1 alpha (HIF-1α), and vascular endothelial growth factor (VEGF) expression in colorectal cancer., Materials and Methods: The tumor tissues of 311 patients with colorectal carcinoma that had undergone potentially curative resections were immunohistochemically assessed using monoclonal antibodies against p53, HIF-1α, and VEGF., Results: Positivity rates of p53, HIF-1α, and VEGF were 42.4%, 63.0%, and 56.6%, respectively. HIF-1α expression in tumor tissues was determined to be correlated significantly with the expression of VEGF (p=0.040), and depth of invasion (p=0.019). Multivariate analysis demonstrated that HIF-1α was independently associated with poor overall survival (p=0.002)., Conclusion: HIF-1α expression is associated with VEGF expression and angiogenesis in colorectal carcinoma. Additionally, the expression of HIF-1α in tumor tissue is associated with angiogenesis and poor overall survival in patients with colorectal cancer.