Injectable Poloxamer Hydrogel Formulations for Intratympanic Delivery of Dexamethasone.

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.

Sex differences in hearing impairment due to diet-induced obesity in CBA/Ca mice.

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-1ß) 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.

Injectable glycol chitosan thermogel formulation for efficient inner ear drug delivery.

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 (Tgel ~ 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 1H 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.

Radiation-Shielding Devices: The Best Combination for Spine Interventional Procedures.

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.

Hearing Impairment in a Mouse Model of Diabetes Is Associated with Mitochondrial Dysfunction, Synaptopathy, and Activation of the Intrinsic Apoptosis Pathway.

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)-Leprdb/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.

Symptom-associated change of motor-related neuromagnetic fields in a patient with multiple sclerosis: A case report.

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.

Scientific rationale for extrapolation of biosimilar data across cancer indications: case study of CT-P10.

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.

Clinical development of CT-P10 and other biosimilar cancer therapeutics.

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.

Looking to the future and learning lessons from the recent past: changing stakeholder perceptions of biosimilars in cancer.

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.

An introduction to biosimilar cancer therapeutics: definitions, rationale for development and regulatory requirements.

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.

Gene expression profiling of hematologic malignant cell lines resistant to oncolytic virus treatment.

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.

Accuracy of MEG in localizing irritative zone and seizure onset zone: Quantitative comparison between MEG and intracranial EEG.

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.

Relationship between insulin-like growth factor axis gene polymorphisms and clinical outcome in advanced gastric cancer patients treated with FOLFOX.

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.

Clinical Usefulness of Hydromorphone-OROS in Improving Sleep Disturbances in Korean Cancer Patients: A Multicenter, Prospective, Open-Label Study.

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.

Chemotherapy in advanced gastric cancer patients associated with disseminated intravascular coagulation.

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.

Decreased inhibitory neuronal activity in patients with frontal lobe brain tumors with seizure presentation: Preliminary study using magnetoencephalography.

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.

'Is tinnitus accompanied by hemifacial spasm in normal-hearing patients also a type of hyperactive neurovascular compression syndrome? : A magnetoencephalography study.

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.

The relationship of vascular endothelial growth factor gene polymorphisms and clinical outcome in advanced gastric cancer patients treated with FOLFOX: VEGF polymorphism in gastric cancer.

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.

US screening for detection of nonpalpable locoregional recurrence after mastectomy.

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.

Prognostic significance of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase expression in biliary tract cancer patients receiving adjuvant 5-fluorouracil-based chemotherapy.

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).