Indicative factors for surgical or angiographic intervention in hemodynamically stable patients with blunt abdominal trauma: A retrospective cohort study.

INTRODUCTION: The standard of care for intraperitoneal injury in hemodynamically stable patients after blunt abdominal trauma has been replaced by non-operative management (NOM). However, selective NOM, depending on the situation, seems necessary in determining the treatment plan. In this study, we attempted to identify risk factors for surgical or angiographic intervention (SAI) in hemodynamically stable blunt abdominal trauma patients. METHODS: This retrospective study which included adult patients who were brought to a regional trauma center was conducted from March 2015 to October 2019. We evaluated the characteristics of blunt abdominal trauma patients and analyzed factors that were related to the requirement of SAI in these patients. Patients were divided into SAI and conservative management (CM) groups. RESULTS: We reviewed 1,176 patients, and after exclusions, of whom 248 blunt abdominal trauma and free fluid observed on CT were identified. The mean pulse rate was higher in the SAI than in the CM (P=0.025). Laboratory findings showed that lactate and delta neutrophil index (DNI) levels were higher in the SAI than in the CM (P=0.002 and 0.026 respectively). Additionally, the mean free fluid size in the SAI (85.69mm) was significantly larger than that in the CM (68.12mm; P=0.001), and blush was more frequently observed in the SAI (P<0.001). In multivariate analysis, only blush was an independent prognostic factor for SAI (OR 11.7, 95% CI, 5.1-30.8, P<0.001). CONCLUSION: In hemodynamically stable patients with blunt abdominal trauma, blush but also high lactate and DNI are associated with the requirement of interventional radiology and/or surgery.

The Resolution Rate of Pulmonary Embolism on CT Pulmonary Angiography: a Prospective Study.

PURPOSE: To prospectively assess the rate of clot resolution from CT pulmonary angiography (CTPA) in patients with acute pulmonary embolism (PE). MATERIALS AND METHODS: This prospective cohort study included 290 patients (136 men, 154 women; mean age, 51.9 years) with acute PE. All patients had a CTPA at the presentation and had at least one follow-up within 6 months (mean 72.7 days). Sixty-four percent of patients had follow-up scans for research purposes within a pre-determined period (between 28 and 184 days; mean, 78.27 days) and 36 % had (between 2 and 184 days; mean, 62.78 days) for a clinical indication. The volume of each clot was measured using a semi-automated quantification program. The resolution rate was evaluated by interval-censored analysis. RESULTS: The overall estimated probability of complete resolution was 42 % at 7 days, 56 % at 10 days, and 71 % at 45 days. Achieving complete resolution was significantly faster in patients with peripheral clots (HR: 1.78; CI: 1.05-3.03, p = 0.032) but slower in patients with consolidation and history of venous thromboembolism (VTE), (HR: 0.37; CI: 0.18-0.79, p = 0.01 and HR: 0.57; CI: 0.35-0.91, p = 0.019, respectively). Although the patients with cancer showed a faster resolution rate (HR: 1.67; CI: 1.05-2.68, p = 0.032), the mortality rate was significantly higher than non-cancer patients. CONCLUSION: The resolution rate of clot burden in acute PE was associated with patients' clinical presentation variables and CTPA imaging biomarkers. This information may be incorporated into designing a prediction rule and determining the appropriate duration of anticoagulation therapy in patients with acute PE.

Onychopapilloma: its clinical, dermoscopic and pathologic features.

BACKGROUND: Onychopapilloma is a benign tumour of the nail bed and distal matrix and commonly presents as longitudinal erythronychia, longitudinal leukonychia or longitudinal melanonychia. Because onychopapilloma is rare, its clinical characteristics and dermoscopic findings have not been well investigated in Asia. OBJECTIVES: This study aimed to investigate the clinical characteristics and dermoscopic and pathologic findings of onychopapilloma in Korea. METHODS: We retrospectively reviewed the medical records and clinical/dermoscopic photographs of 39 patients diagnosed with onychopapilloma in the Pusan National University Hospitals (Busan and Yangsan) for 11 years (2010-2021). RESULTS: Among 39 patients, 23 (59.0%) were men, and 16 (41.0%) were women. The mean age was 46.1 (16-77) years. All lesions were single, and most of them were located on the fingers (92.3%), especially the thumb (66.7%). The most common clinical feature was longitudinal erythronychia (56.4%), and the most common dermoscopic finding was distal subungual hyperkeratosis (100%). We found two new dermoscopic features: macrolunula and trailing lunula along the longitudinal band. Among 18 patients who underwent surgical excision, only 6 (33.3%) showed typical acanthosis and papillomatosis on the nail bed. CONCLUSIONS: We found that Asian onychopapilloma has similar clinicodermoscopic findings to the Caucasian one, that is to say, longitudinal erythronychia and distal subungual hyperkeratosis were the most common nail change and dermoscopic finding, respectively. We propose two new dermoscopic features of onychopapilloma: macrolunula and trailing lunula along the longitudinal band.

Two-photon graphene quantum dot modified Gd2O3 nanocomposites as a dual-mode MRI contrast agent and cell labelling agent.

For obtaining high-resolution macroscopical anatomical information and high sensitivity microscopical optical signals, it is highly desirable to develop dual-modality magnetic resonance imaging (MRI) and fluorescent probes in medical imaging simultaneously. In this study, Gd2O3 nanoparticles were modified with two-photon graphene quantum dots (GQD), integrating a magnetic resonance imaging (MRI) contrast agent with two-photon imaging functionality into one nanoprobe. A photoluminescence study indicated that the GQD modification process integrated MRI properties with both one-photon and two-photon imaging properties. Gd2O3/GQD nanocomposites showed a significantly improved longitudinal relaxivity (r1 = 15.995 mM-1 s-1) in comparison with commercial Magnevist (Gd-DTPA, r1 = 4.5 mM-1 s-1) and some reported papers. Excellent water solubility and good biocompatibility make Gd2O3/GQD nanocomposites an ideal dual-modal imaging agent, suggesting their potential and significant biological and clinical applications in the future.

LAPAROSCOPIC OVARIECTOMY IN THE ASIATIC BLACK BEAR (URSUS THIBETANUS) WITH THE USE OF THE SONICISION™ DEVICE.

Laparoscopic ovariectomy was performed in two Asiatic black bears ( Ursus thibetanus ). Bears were placed in a 20° Trendelenburg position on a surgical table. A three-portal technique was used. A camera port was established 10 cm caudal to the umbilicus with a 5-mm cannula. Two instrument ports were made 1 cm caudal to the umbilicus with a 5-mm cannula and 8 cm caudal to the camera port with a 12-mm cannula, respectively. The suspensory ligament, ovarian vasculature, and uterine horn tip were progressively dissected following coagulation with the Sonicision™ cordless ultrasonic dissection device. The resected ovary was exteriorized through the 12-mm instrument portal site but enlarged to a 2-cm incision length. The abdominal musculature, subcutaneous tissue, and skin of the portal sites were closed separately. Total surgical time was 113 min (Bear A) and 49 min (Bear B), and no postoperative complications were encountered. This is the first report of laparoscopic ovariectomy in the Asiatic black bear.

Analysis of contrast time-enhancement curves to optimise CT pulmonary angiography.

AIM: To assess enhancement profiles of the pulmonary artery (PA) and determine optimal scan timing in PA computed tomography (CT) angiography. MATERIALS AND METHODS: One hundred consecutive patients referred for contrast-enhanced chest CT were prospectively studied. Fifteen low-radiation monitoring images were acquired at 2-second intervals, 5 seconds after the start of an injection of 370 mg iodine/I contrast medium for 1 ml/kg of body weight injected over 20 seconds. Contrast time-enhancement data were measured over the PA. The time and magnitude of peak as well as times to five different enhancement thresholds (50, 100, 150, 200, 250 HU) were calculated. A set of candidate fixed and circulation-adjusted scan delays were analysed and compared in terms of the quality of contrast enhancement over the 4-second diagnostic scan duration. RESULTS: The mean degree of peak PA enhancements was 431.4±65.2HU (range, 263.8-575.3HU). The mean time to peak enhancement was 22.4±3.1 seconds (range, 11-27 seconds). From potential fixed delays ranging 11-27 seconds, 19 seconds showed the highest enhancement quality. For the circulation-adjusted delays, the combination of 150 HU bolus-track threshold with diagnostic delay of 10 seconds had the highest enhancement quality. CONCLUSION: Peak enhancement of PA occurred, on average, right after completion of contrast injection for 20 seconds. The fixed scan delay of 19 seconds or circulation-adjusted delay with the bolus-threshold of 150 HU and diagnostic delay of 10 seconds appear optimal.

Intracellular annexin A2 regulates NF-κB signaling by binding to the p50 subunit: implications for gemcitabine resistance in pancreatic cancer.

Annexin A2 (ANXA2) expression is highly upregulated in many types of cancer. Although cell surface localization of ANXA2 has been reported to have a critical role in the progression and metastasis of a variety of tumors, including pancreatic cancer, the biological role of intracellular ANXA2 is not fully understood. Herein the role of intracellular ANXA2 was investigated in a pancreatic cancer cell line. We first determined whether ANXA2 is involved in NF-κB signaling pathways. ANXA2 bound to the p50 subunit of NF-κB in a calcium-independent manner, and the ANXA2-p50 complex translocated into the nucleus. Furthermore, ANXA2 increased the transcriptional activity of NF-κB in both the resting and activated states and upregulated the transcription of several target genes downstream of NF-κB, including that encoding interleukin (IL)-6, which contributes to anti-apoptotic signaling. In Mia-Paca2 cells, we determined the effects of wild-type ANXA2 and an ANXA2 mutant, Y23A, which suppresses the cell surface localization, on upregulation of NF-κB transcriptional activity and secretion of IL-6. Both wild-type and Y23A ANXA2 induced anti-apoptotic effects in response to treatment with tumor necrosis factor-α or gemcitabine. Based on these results, we suggest that ANXA2 mediates resistance to gemcitabine by directly increasing the activity of NF-κB. Collectively, these data may provide additional information about the biological role of ANXA2 in pancreatic cancer and suggest that ANXA2 is a potential biomarker for the drug resistance phenotype and a candidate therapeutic target for the treatment of pancreatic cancer.

Unilateral laparoscopic ovariectomy in a red fox (Vulpes vulpes) with an ovarian cyst.

Unilateral laparoscopic ovariectomy was attempted in a red fox (Vulpes vulpes) with an ovarian cyst through single portal access. The ovarian cyst was resistant to conservative therapy using gonadotropin-releasing hormone. A 10-mm laparoscope with an operating channel was introduced into the abdomen via a 12-mm umbilical portal. The left ovary and cyst (34.1 x 30.8 mm) were fixed to the left abdominal wall by a transabdominal suspension suture. The ovarian pedicles and ligaments were progressively cauterized and transected with a multifunction bipolar electrocoagulation forceps. The resected cystic ovary was exteriorized through the umbilical portal site. The surgical time was 42 min, and no intra- and postoperative complications were encountered. Two months after the surgery mating was observed, and the fox gave birth to three healthy cubs 56 days after the mating. This is the first report of using laparoscopy in the red fox with an ovarian cyst.

The relationship of trigger finger and flexor tendon volar migration after carpal tunnel release.

It has been suggested that the increased frequency of trigger finger (TF) after carpal tunnel release (CTR) may be caused by the volar migration of the flexor tendons at the wrist altering the tendon biomechanics at the A1 pulley. This hypothesis has not been validated. We performed pre- and post-operative ultrasonography (USG) on the affected wrists of 92 patients who underwent CTR. Pre-operative USG was performed in neutral with no tendon loading; post-operative USG was performed in neutral unloaded and in various positions of wrist flexion whilst loading the flexor tendons with gripping. The mean volar migration of the flexor tendons after CTR was 2.2 (SD 0.4) mm in the unloaded neutral position. It was 1.8 (SD 0.4) mm in patients who did not develop TF and 2.5 (SD 0.5) mm in those who did (p = 0.0067). In loaded wrist flexion, the mean volar migration of flexor tendons after CTR in patients who did not develop TF and those who did was 2.1 and 3.0 mm in 0° flexion; 3.2 and 3.9 mm in 15° flexion; 4.3 and 5.1 mm in 30° flexion; and 4.9 and 5.8 mm in 45° flexion, respectively. There were significant differences between patients with and without TF at each flexion angle. Our data indicate that patients with greater volar migration of the flexor tendons after CTR are more likely to develop TF. This conclusion supports the hypothesis that the occurrence of TF after CTR may be caused by the bowstringing effects of the flexor tendons.

Evaluation of female hormone-related symptoms in women undergoing carpal tunnel release.

As carpal tunnel syndrome is more common in women, particularly around the menopause, female-related risk factors are suspected to play a role in its pathogenesis. We have assessed whether female hormone-related symptoms are associated with upper extremity disabilities in women undergoing carpal tunnel release. A total of 92 women with a mean age of 53 years scheduled for surgery for carpal tunnel syndrome were assessed preoperatively for female hormone-related symptoms using the menopausal rating scale and other female-related factors such as menopausal status, pregnancy number and serum female hormone levels. Upper extremity disability was evaluated using the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. DASH scores had a moderate correlation with total menopausal rating scale scores, but not with other female-related factors assessed. This study suggests that female hormone-related symptoms are associated with subjective upper extremity disabilities in women with carpal tunnel syndrome. This information may be helpful in addressing patients' complex symptoms or interpretation of outcomes in women with carpal tunnel syndrome.

Inguinal approach for the management of unilateral non-palpable testis: is diagnostic laparoscopy necessary?

OBJECTIVE: During the last decade laparoscopy has increasingly been advocated as the primary investigative procedure for the management of the non-palpable testis. We reviewed the medical records in a consecutive series of boys with non-palpable testis to examine the contribution of the initial inguinal approach in the management of unilateral non-palpable testis. MATERIALS AND METHODS: Among the 183 consecutive patients with cryptorchidism from 2003 to 2012, there were 21 patients with unilateral and three with bilateral non-palpable testes. All unilateral patients then underwent inguinal and scrotal exploration through an inguinal incision. For those patients with an intra-abdominal peeping testis, the gonad was placed into the scrotum after meticulous cranial mobilization of the spermatic cord. RESULTS: Patient age ranged from 11 months to 144 months (mean age: 23 months). Among the 21 unilateral cases, testicular absence or atrophy was confirmed in seven patients with a scrotal nubbin in six, and blind-ending vas and vessels at the external inguinal ring in one patient. Among the remaining 14 patients with sizeable testes, 12 testes were intra-abdominal peeping testes and two testicles were seen within the distal inguinal canal, which may be missed on physical examination owing to patient obesity. The intra-abdominal peeping testicle had the opened processus vaginalis entering the internal ring in which testicle was found. These were fixed into the scrotum successfully by cranial mobilization of spermatic vessel sometimes cutting the internal oblique muscle and by Prentiss and Fowler-Stephen's maneuver. Diagnostic laparoscopy was done on three patients with bilateral cases. CONCLUSIONS: Given the result that most of nubbins are within the scrotum and testes with intra-abdominal peeping testes are fixed down safely into the scrotum, the inguinal approach may suffice for the management of unilateral non-palpable testis. Laparoscopy should be reserved for patients with bilateral non-palpable undescended testes.

Image quality and radiation exposure in CT of the pancreas: 320-MDCT with and without adaptive iterative dose reduction versus 64-MDCT.

AIM: To compare the image quality and radiation exposure in computed tomography (CT) of the pancreas acquired using 320-multidetector (MD)CT versus 64-MDCT and to demonstrate the effects of adaptive iterative dose reduction (AIDR) on 320-MDCT. MATERIALS AND METHODS: One hundred and fifty patients were randomized into three groups including 320-section volume imaging using AIDR (group A), 320-slice volume scan without AIDR (group B), and 64-section helical imaging without AIDR (group C). Transaxial arterial, pancreatic phase, and volume-rendered CT angiographic images were reconstructed. CT radiodensity of the abdominal aorta, pancreas, signal-to-noise ratios (SNR), dose-length products (DLPs; mGy cm), and image quality were measured. RESULTS: No significant difference in CT radiodensity of the abdominal aorta or pancreas was noted between groups. Mean DLPs were 600.9 ± 145.8, 681.6 ± 97.5, and 1231.5 ± 271.4 in groups A, B, and C, respectively. The DLP was reduced by 51% in group A and 45% in group B compared to group C (p < 0.001). SNRs of the pancreas during the pancreatic phase were comparable between groups A and C, but were significantly lower in group B (p < 0.001). Image quality, including the depiction of some small arterial branches on the arterial and CT angiographic images and the main pancreatic duct on the pancreatic-phase images, were significantly lower in group B than in groups A and C (p = 0.008-0.038). CONCLUSION: Radiation dose can be markedly reduced for contrast-enhanced CT imaging of the pancreas without compromising image quality using a 320-MDCT with AIDR, compared with 64-section helical CT.

Detected renal cysts are tips of the iceberg in adults with ADPKD.

BACKGROUND AND OBJECTIVES: In autosomal dominant polycystic kidney disease, progressive renal enlargement secondary to expanding cysts is a hallmark. The total cyst load and range of cyst diameters are unknown. The purpose of this study was to quantify the total number and range of diameters of individual cysts in adults with preserved GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A retrospective, morphometric analysis of renal cyst number and diameter using magnetic resonance images from eight adult autosomal dominant polycystic kidney disease patients was performed at baseline and after 6.9 years. Cyst number and diameter were measured in microscopic sections of nephrectomy specimens from five different adults. RESULTS: The diameters of 1010 cysts ranged from 0.9 to 77.1 mm in baseline T2 magnetic resonance images, and the mean total number of cysts increased from 682 to 1002 in 6.9 years. However, magnetic resonance imaging detects only cysts above the lower limit of detection. In 405 cysts measured in nephrectomy specimens, 70% had diameters <0.9 mm. Cyst counts by magnetic resonance in eight subjects compared with histology revealed approximately 62 times more cysts below the limit of magnetic resonance imaging detection than above it. CONCLUSIONS: This study presents quantitative data indicating that renal cysts develop in a minority of renal tubules. Increased numbers detected by magnetic resonance imaging are caused primarily by cysts below detection at baseline enlarging to a detectable diameter over time. The broad range of diameters, with a heavy concentration of microscopic cysts, may be most appropriately explained by a formation process that operates continuously throughout life.

Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: RTOG 9704.

The aim of this study is to validate the prognostic and predictive value of the non-synonymous cytidine deaminase (CDA) Lys²7Gln polymorphism for hematological toxicity and survival using a randomized phase III adjuvant trial (Radiation Therapy Oncology Group (RTOG) 9704) in pancreatic cancer in which one treatment arm received gemcitabine. CDA is involved in gemcitabine inactivation, and there is conflicting data on the role of the non-synonymous CDA Lys²7Gln polymorphism in predicting toxicity and survival in cancer patients treated with gemcitabine. RTOG 9704 randomized 538 patients after pancreatic resection to receive radiotherapy with either 5-fluorouracil (5-FU) or gemcitabine. CDA Lys²7Gln polymorphism genotype was analyzed. We tested an association between CDA single-nucleotide polymorphism genotype and the survival outcome by the Cox proportional hazard model adjusting for other covariates, as well as toxicity by the logistic regression model. There is statistically significant more severe hematological toxicity in patients treated with gemcitabine with either the homozygote wild-type genotype (Lys/Lys) alone (odds ratio (OR)=0.06, P=0.01), or in combination with the heterozygote (Lys/Gln; OR=0.14, P=0.03) when compared with homozygote variant genotype (Gln/Gln) when adjusted for other covariates. This was not seen in the non-gemcitabine treated arm. There are no genotype differences with respect to survival outcome. In conclusion, in this prospective randomized adjuvant study of patients with pancreatic cancer, the CDA Lys²7Gln polymorphism is validated as a predictive marker of gemcitabine hematological toxicity, but not with treatment response or survival.

The revised Atlanta classification for acute pancreatitis: a CT imaging guide for radiologists.

Accurate diagnosis and description of the various findings in acute pancreatitis is important for treatment. The original Atlanta classification for acute pancreatitis sought to create a uniform system for classifying the severity of acute pancreatitis as well as common language to describe the various events that can occur in acute pancreatitis. The goal was to allow accurate communication between physicians using standardized language so correct treatment options could be used. Since that time, advances in the understanding of acute pancreatitis as well as improvements in both interventions and imaging have led to criticisms of the system and its abandonment by physicians. A 2007 revision of the Atlanta classifications sought to address many of these issues. This article will explain the changes to the Atlanta classification system and provide pictorial examples of the findings in acute pancreatitis as described by the Atlanta classification system.

Analysis of baseline parameters in the HALT polycystic kidney disease trials.

HALT PKD consists of two ongoing randomized trials with the largest cohort of systematically studied patients with autosomal dominant polycystic kidney disease to date. Study A will compare combined treatment with an angiotensin-converting inhibitor and receptor blocker to inhibitor alone and standard compared with low blood pressure targets in 558 early-stage disease patients with an eGFR over 60 ml/min per 1.73 m(2). Study B will compare inhibitor-blocker treatment to the inhibitor alone in 486 late-stage patients with eGFR 25-60 ml/min per 1.73 m(2). We used correlation and multiple regression cross-sectional analyses to determine associations of baseline parameters with total kidney, liver, or liver cyst volumes measured by MRI in Study A and eGFR in both studies. Lower eGFR and higher natural log-transformed urine albumin excretion were independently associated with a larger natural log-transformed total kidney volume adjusted for height (ln(HtTKV)). Higher body surface area was independently associated with a higher ln(HtTKV) and lower eGFR. Men had larger height-adjusted total kidney volume and smaller liver cyst volumes than women. A weak correlation was found between the ln(HtTKV) and natural log-transformed total liver volume adjusted for height or natural log liver cyst volume in women only. Women had higher urine aldosterone excretion and lower plasma potassium. Thus, our analysis (1) confirms a strong association between renal volume and functional parameters, (2) shows that gender and other factors differentially affect the development of polycystic disease in the kidney and liver, and (3) suggests an association between anthropomorphic measures reflecting prenatal and/or postnatal growth and disease severity.

Patterns of missing mini mental status exam (MMSE) in radiation therapy oncology group (RTOG) brain cancer trials.

The Mini Mental Status Exam (MMSE) instrument has been commonly used in the Radiation Therapy Oncology Group (RTOG) to assess mental status in brain cancer patients. Evaluating patient factors in relation to patterns of incomplete MMSE assessments can provide insight into predictors of missingness and optimal MMSE collection schedules in brain cancer clinical trials. This study examined eight RTOG brain cancer trials with ten treatment arms and 1,957 eligible patients. Patient data compliance patterns were categorized as: (1) evaluated at all time points (Complete), (2) not evaluated from a given time point or any subsequent time points but evaluated at all the previous time points (Monotone drop-out), (3) not evaluated at any time point (All missing), and (4) all other patterns (Mixed). Patient characteristics and reasons for missingness were summarized and compared among the missing pattern groups. Baseline MMSE scores and change scores after radiation therapy (RT) were compared between these groups, adjusting for differences in other characteristics. There were significant differences in frequency of missing patterns by age, treatment type, education, and Zubrod performance status (ZPS; P < 0.001). Ninety-two percent of patients were evaluated at least once: seven percent of patients were complete pattern, 49% were Monotone pattern, and 36% were mixed pattern. Patients who received RT only regimens were evaluated at a higher rate than patients who received RT + other treatments (49-64% vs. 27-45%). Institutional error and request to not be contacted were the most frequent known reasons for missing data, but most often, reasons for missing MMSE was unspecified. Differences in baseline mean MMSE scores by missing pattern (Complete, Monotone dropout, Mixed) were statistically significant (P < 0.001) but differences were small (<1.5 points) and significance did not persist after adjustment for age, ZPS, and other factors related to missingness. Post-RT change scores did not differ significantly by missing pattern. While baseline and change scores did not differ widely by missing pattern for available measurements, incomplete data was common and of unknown reason, and has potential to substantially bias conclusions. Higher compliance rates may be achievable by addressing institutional compliance with assessment schedules and patient refusal issues, and further exploration of how educational and health status barriers influence compliance with MMSE and other tools used in modern neurocognitive batteries.

Phase II study of S-1 combined with oxaliplatin as therapy for patients with metastatic biliary tract cancer: influence of the CYP2A6 polymorphism on pharmacokinetics and clinical activity.

BACKGROUND: Advanced biliary cancer is often treated with fluoropyrimidine-based chemotherapy. In this study, we evaluated the efficacy and tolerability of a combination of S-1, an oral fluoropyrimidine prodrug, and oxaliplatin in patients with metastatic biliary cancer. METHODS: Patients with histologically confirmed metastatic biliary cancer and no history of radiotherapy or chemotherapy were enrolled. Oxaliplatin was administered intravenously (130 mg m(-2)), followed by 14-day administration of oral S-1 (40 mg m(-2) twice daily) with a subsequent 7-day rest period every 21 days. Pharmacokinetic analysis of S-1 was performed at cycle 1. Patients were genotyped for CYP2A6 polymorphisms ((*)1, (*)4, (*)7, (*)9 or (*)10), and pharmacokinetic and clinical parameters compared according to the CYP2A6 genotype. RESULTS: In total, 49 patients were evaluated, who received a median of four cycles. The overall response rate was 24.5%. Median progression-free and overall survival was 3.7 and 8.7 months, respectively. The most common haematological grade 3 out of 4 toxicity was neutropenia (14%), while non-hematological grade 3 out of 4 toxicities included anorexia (14%), nausea (12%), asthenia (10%), vomiting (10%), and diarrhoea (4%). Biotransformation of S-1 (AUC(0-24 h) of 5-fluorouracil/AUC(0-24 h) of tegafur) was 1.85-fold higher for the *1/*1 group than for the other groups (90% confidence interval 1.37-2.49). Diarrhoea (P=0.0740), neutropenia (P=0.396), and clinical efficacy (response rate, P=0.583; PFS, P=0.916) were not significantly associated with CYP2A6 genotype, despite differences in 5-FU exposure. CONCLUSION: The combination of S-1 and oxaliplatin appears to be active and well tolerated in patients with metastatic biliary cancer, and thus is feasible as a therapeutic modality. CYP2A6 genotypes are associated with differences in the biotransformation of S-1. However, the impact of the CYP2A6 polymorphism on variations in clinical efficacy or toxicity requires further evaluation.

Antitumor activity of Ad-IU2, a prostate-specific replication-competent adenovirus encoding the apoptosis inducer, TRAIL.

In this study, we analyzed the preclinical utility and antitumor efficacy of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) delivered by Ad-IU2, a prostate-specific replication-competent adenovirus (PSRCA), against androgen-independent prostate cancer. Through transcriptional control of adenoviral early genes E1a, E1b and E4, as well as TRAIL by two bidirectional prostate-specific enhancing sequences (PSES), the expression of TRAIL and adenoviral replication was limited to prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA)-positive cells. Ad-IU2 induced fivefold greater apoptosis selectively in PSA/PSMA-positive CWR22rv and C4-2 cells than an oncolytic adenoviral control. Furthermore, prolonged infection with Ad-IU2 reversed TRAIL resistance in LNCaP cells. Ad-IU2 showed superior killing efficiency in PSA/PSMA-positive prostate cancer cells at doses five- to eight-fold lower than required by a PSRCA to produce a similar effect; however, this cytotoxic effect was not observed in non-prostatic cells. As an enhancement of its therapeutic efficacy, Ad-IU2 exerted a TRAIL-mediated bystander effect through direct cell-to-cell contact and soluble factors such as apoptotic bodies. In vivo, Ad-IU2 markedly suppressed the growth of subcutaneous androgen-independent CWR22rv xenografts compared with a PSRCA at 6 weeks after treatment (3.1- vs 17.1-fold growth of tumor). This study shows the potential clinical utility of a PSRCA armed with an apoptosis-inducing ligand.

VDUP1 potentiates Ras-mediated angiogenesis via ROS production in endothelial cells.

Vitamin D3 up-regulated protein 1 (VDUP1) is a tumor suppressor of which expression is reduced in a variety of cancer cells, and enforced expression inhibits the tumor cell proliferation. It inhibits the activity of thioredoxin, thus contributing cellular ROS generation. Since ROS is a critical factor for angiogenesis, we investigated the role of VDUP1 in angiogenesis and endothelial proliferation. The expression of VDUP1 was upregulated by overexpression of an oncogene, Ras. Enforced expression of VDUP1 increases ROS production and proliferation of Ras-overexpressing endothelial cells. Overexpression of VDUP1 increases the resistance to the anchorage-dependent cell death and tube formation of the Ras-overexpressing endothelial cell. In addition, the removal of ROS by ROS scavenger attenuates the effect of VDUP1 on tube formation. These results suggest that VDUP1 is involved in Ras-mediated angiogenesis via ROS generation in endothelial cells.