Capecitabine plus temozolomide in patients with grade 3 unresectable or metastatic gastroenteropancreatic neuroendocrine neoplasms with Ki-67 index <55%: single-arm phase II study.

BACKGROUND: Grade 3 neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) origin with Ki-67 indices <55% do not respond well to platinum-based chemotherapy. The combination of capecitabine and temozolomide (CAPTEM) has shown favorable responses in grade 1-2 NENs, but has rarely been studied in patients with grade 3 NENs. PATIENTS AND METHODS: This open-label, single-arm phase II trial included patients with unresectable or metastatic grade 3 NENs of GEP origin with Ki-67 indices <55% enrolled between June 2017 and July 2020. Patients received oral capecitabine 750 mg/m2 twice daily on days 1 to 14 and oral temozolomide 200 mg/m2 once daily on days 10 to 14 every 4 weeks. Histologic findings were centrally reviewed after the completion of enrollment. The primary endpoint was overall response rate, and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: Of the 30 patients included in the full analysis set, 1 (3.3%) achieved complete response, 8 (26.7%) had partial responses, and 14 (46.7%) had stable disease, making the overall response rate 30.0%. At a median follow-up of 19.2 months, the median PFS was 5.9 months and the median OS was not reached. Patients with well-differentiated NENs showed significantly better median PFS (9.3 months versus 3.5 months, P = 0.005) and median OS (not reached versus 6.2 months, P = 0.004) than patients with poorly differentiated tumors. Expression of O6-methyl-guanine methyltransferase protein did not correlate with clinical outcomes. The most common grade 3-4 adverse events were thrombocytopenia (10%), anemia (6.7%), and nausea (6.7%). CONCLUSIONS: CAPTEM was effective and well tolerated in patients with grade 3 GEP-NENs with Ki-67 indices <55%, with superior efficacy outcomes compared with the historical controls receiving platinum-based chemotherapy.

Changes in blood and urinary cadmium levels and bone mineral density according to osteoporosis medication in individuals with an increased cadmium body burden.

The aim of this study was to assess changes in bone mineral density (BMD) and cadmium (Cd) levels in blood and urine in individuals living in a Cd-contaminated area according to the type of osteoporosis medication over a three-year period. This follow-up study included 204 residents living in the vicinity of a closed copper refinery, who had been found to have elevated urinary or blood Cd levels. Cd levels in the blood and urine, as well as BMD, were measured every 6 months. After the first BMD measurement, individuals were prescribed antiresorptives such as alendronate or vitamin D and calcium, according to their BMD. Subjects were classified according to the type of medicine provided over the previous 6 months. General linear models controlling for other factors were used to evaluate the effects of each type of medication on the participants' Cd levels and BMD. Spinal BMD showed a significant increase in the antiresorptive group compared to the nontreatment group. Significant decreases in blood Cd levels were found in the vitamin D and calcium group, in comparison to the nontreatment group, as well as a marginally significant decrease in the antiresorptive group. The vitamin D and calcium group showed a significantly greater decrease in urinary Cd levels than the nontreatment group. In contrast, antiresorptive medication was found to have a negative effect on urinary Cd excretion. These results suggest that vitamin D and calcium treatment for osteoporosis lowers blood Cd levels more effectively and improves urinary Cd excretion.

A review of recent advances in the spherical harmonics expansion method for semiconductor device simulation.

The Boltzmann transport equation is commonly considered to be the best semi-classical description of carrier transport in semiconductors, providing precise information about the distribution of carriers with respect to time (one dimension), location (three dimensions), and momentum (three dimensions). However, numerical solutions for the seven-dimensional carrier distribution functions are very demanding. The most common solution approach is the stochastic Monte Carlo method, because the gigabytes of memory requirements of deterministic direct solution approaches has not been available until recently. As a remedy, the higher accuracy provided by solutions of the Boltzmann transport equation is often exchanged for lower computational expense by using simpler models based on macroscopic quantities such as carrier density and mean carrier velocity. Recent developments for the deterministic spherical harmonics expansion method have reduced the computational cost for solving the Boltzmann transport equation, enabling the computation of carrier distribution functions even for spatially three-dimensional device simulations within minutes to hours. We summarize recent progress for the spherical harmonics expansion method and show that small currents, reasonable execution times, and rare events such as low-frequency noise, which are all hard or even impossible to simulate with the established Monte Carlo method, can be handled in a straight-forward manner. The applicability of the method for important practical applications is demonstrated for noise simulation, small-signal analysis, hot-carrier degradation, and avalanche breakdown.

Real-time prediction and gating of respiratory motion in 3D space using extended Kalman filters and Gaussian process regression network.

The prediction as well as the gating of respiratory motion have received much attention over the last two decades for reducing the targeting error of the radiation treatment beam due to respiratory motion. In this article, we present a real-time algorithm for predicting respiratory motion in 3D space and realizing a gating function without pre-specifying a particular phase of the patient's breathing cycle. The algorithm, named EKF-GPRN(+) , first employs an extended Kalman filter (EKF) independently along each coordinate to predict the respiratory motion and then uses a Gaussian process regression network (GPRN) to correct the prediction error of the EKF in 3D space. The GPRN is a nonparametric Bayesian algorithm for modeling input-dependent correlations between the output variables in multi-output regression. Inference in GPRN is intractable and we employ variational inference with mean field approximation to compute an approximate predictive mean and predictive covariance matrix. The approximate predictive mean is used to correct the prediction error of the EKF. The trace of the approximate predictive covariance matrix is utilized to capture the uncertainty in EKF-GPRN(+) prediction error and systematically identify breathing points with a higher probability of large prediction error in advance. This identification enables us to pause the treatment beam over such instances. EKF-GPRN(+) implements a gating function by using simple calculations based on the trace of the predictive covariance matrix. Extensive numerical experiments are performed based on a large database of 304 respiratory motion traces to evaluate EKF-GPRN(+) . The experimental results show that the EKF-GPRN(+) algorithm reduces the patient-wise prediction error to 38%, 40% and 40% in root-mean-square, compared to no prediction, at lookahead lengths of 192 ms, 384 ms and 576 ms, respectively. The EKF-GPRN(+) algorithm can further reduce the prediction error by employing the gating function, albeit at the cost of reduced duty cycle. The error reduction allows the clinical target volume to planning target volume (CTV-PTV) margin to be reduced, leading to decreased normal-tissue toxicity and possible dose escalation. The CTV-PTV margin is also evaluated to quantify clinical benefits of EKF-GPRN(+) prediction.

Prevalence and clinical significance of cellular and acellular mucin in patients with locally advanced mucinous rectal cancer who underwent preoperative chemoradiotherapy followed by radical surgery.

AIM: The frequent presence of acellular mucin in specimens showing pathological complete response to preoperative chemoradiotherapy (CRT) and the poor response to preoperative CRT in mucinous rectal cancer have been reported. However, the prevalence and prognostic significance of cellular and acellular mucin have not been evaluated in resected specimens from patients with mucinous rectal cancer who undergo preoperative CRT. METHOD: We retrospectively evaluated the clinicopathological features and prognostic significance of mucin in resected specimens from 59 consecutive patients with mucinous rectal cancer who underwent long-course CRT followed by resection between January 2000 and December 2009. Patients were categorized according to the presence of mucin, as identified by pathological analysis. The clinicopathological findings and oncological results were compared. RESULTS: Mucin was identified in 25 of 59 patients with mucinous rectal cancer (42.4%). Mucin was more frequent in men (hazard ratio = 23.94, 95% confidence interval = 1.875-305.504, P = 0.015) and in specimens showing a good tumour response grade (hazard ratio = 64.26, 95% confidence interval = 6.940-595.045, P < 0.001). With a median follow-up of 67.7 (range 8.6-133.2) months, the 5-year overall survival (60.7% without mucin vs 51.4% with mucin, P = 0.898) and disease-free survival (59.9% without mucin vs 56.9% with mucin, P = 0.813) did not differ between the groups. CONCLUSION: The presence of mucin in rectal cancer with mucinous differentiation after preoperative CRT and resection is associated with male gender and a good tumour response grade, without significant impact on oncological outcome.

NAMPT suppresses glucose deprivation-induced oxidative stress by increasing NADPH levels in breast cancer.

Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme involved in NAD+ biosynthesis. Although NAMPT has emerged as a critical regulator of metabolic stress, the underlying mechanisms by which it regulates metabolic stress in cancer cells have not been completely elucidated. In this study, we determined that breast cancer cells expressing a high level of NAMPT were resistant to cell death induced by glucose depletion. Furthermore, NAMPT inhibition suppressed tumor growth in vivo in a xenograft model. Under glucose deprivation conditions, NAMPT inhibition was found to increase the mitochondrial reactive oxygen species (ROS) level, leading to cell death. This cell death was rescued by treatment with antioxidants or NAD+. Finally, we showed that NAMPT increased the pool of NAD+ that could be converted to NADPH through the pentose phosphate pathway and inhibited the depletion of reduced glutathione under glucose deprivation. Collectively, our results suggest a novel mechanism by which tumor cells protect themselves against glucose deprivation-induced oxidative stress by utilizing NAMPT to maintain NADPH levels.

Clinical implications of mucinous components correlated with microsatellite instability in patients with colorectal cancer.

AIM: Colorectal cancer (CRC) with microsatellite instability (MSI) is characterized by frequent poor differentiation or mucinous histology. The purpose of this study was to evaluate the association of MSI with clinicopathological features and the oncological outcome in patients with a mucinous component. METHOD: CRC tissue samples were analysed for histology and MSI. Patients were grouped according to the mucinous content of the tumour, as follows: > 50%, mucinous adenocarcinoma (MA); ≤ 50%, adenocarcinoma with mucinous component (AMC); none, nonmucinous adenocarcinoma (NMA). Clinicopathological parameters and survival were compared between patient groups. RESULTS: Of 2025 patients, 84 (4%) had MA and 124 (6%) had AMC. In addition, 202 (10%) had MSI. Patients with MA and AMC tended to have a younger age of onset, right-colon predilection, large-sized tumour and high frequency of MSI compared with those with NMA (P < 0.001). MA and AMC patients with MSI showed a trend towards right-colon predilection and infrequent lymph-node metastasis compared with those with microsatellite stability (MSS; P = 0.005-0.03). There were no survival differences between the three groups, but patients with MSI-MA demonstrated lower 4-year recurrence and better overall survival rates than those with MSS-MA (P = 0.018 and P = 0.046, respectively). CONCLUSION: Clinicopathological features of AMC and MA were similar and closely associated with MSI status. Although the prognoses of AMC and MA were no different from that of NMA, survival of patients with an MSI-MA tumour was significantly better than for those with MSS-MA tumours.

Real-time prediction and gating of respiratory motion using an extended Kalman filter and Gaussian process regression.

Motion-adaptive radiotherapy aims to deliver a conformal dose to the target tumour with minimal normal tissue exposure by compensating for tumour motion in real time. The prediction as well as the gating of respiratory motion have received much attention over the last two decades for reducing the targeting error of the treatment beam due to respiratory motion. In this article, we present a real-time algorithm for predicting and gating respiratory motion that utilizes a model-based and a model-free Bayesian framework by combining them in a cascade structure. The algorithm, named EKF-GPR(+), implements a gating function without pre-specifying a particular region of the patient's breathing cycle. The algorithm first employs an extended Kalman filter (LCM-EKF) to predict the respiratory motion and then uses a model-free Gaussian process regression (GPR) to correct the error of the LCM-EKF prediction. The GPR is a non-parametric Bayesian algorithm that yields predictive variance under Gaussian assumptions. The EKF-GPR(+) algorithm utilizes the predictive variance from the GPR component to capture the uncertainty in the LCM-EKF prediction error and systematically identify breathing points with a higher probability of large prediction error in advance. This identification allows us to pause the treatment beam over such instances. EKF-GPR(+) implements the gating function by using simple calculations based on the predictive variance with no additional detection mechanism. A sparse approximation of the GPR algorithm is employed to realize EKF-GPR(+) in real time. Extensive numerical experiments are performed based on a large database of 304 respiratory motion traces to evaluate EKF-GPR(+). The experimental results show that the EKF-GPR(+) algorithm effectively reduces the prediction error in a root-mean-square (RMS) sense by employing the gating function, albeit at the cost of a reduced duty cycle. As an example, EKF-GPR(+) reduces the patient-wise RMS error to 37%, 39% and 42% in percent ratios relative to no prediction for a duty cycle of 80% at lookahead lengths of 192 ms, 384 ms and 576 ms, respectively. The experiments also confirm that EKF-GPR(+) controls the duty cycle with reasonable accuracy.

Real-time prediction of respiratory motion using a cascade structure of an extended Kalman filter and support vector regression.

The motion of thoracic and abdominal tumours induced by respiratory motion often exceeds 20 mm, and can significantly compromise dose conformality. Motion-adaptive radiotherapy aims to deliver a conformal dose distribution to the tumour with minimal normal tissue exposure by compensating for the tumour motion. This adaptive radiotherapy, however, requires the prediction of the tumour movement that can occur over the system latency period. In general, motion prediction approaches can be classified into two groups: model-based and model-free. Model-based approaches utilize a motion model in predicting respiratory motion. These approaches are computationally efficient and responsive to irregular changes in respiratory motion. Model-free approaches do not assume an explicit model of motion dynamics, and predict future positions by learning from previous observations. Artificial neural networks (ANNs) and support vector regression (SVR) are examples of model-free approaches. In this article, we present a prediction algorithm that combines a model-based and a model-free approach in a cascade structure. The algorithm, which we call EKF-SVR, first employs a model-based algorithm (named LCM-EKF) to predict the respiratory motion, and then uses a model-free SVR algorithm to estimate and correct the error of the LCM-EKF prediction. Extensive numerical experiments based on a large database of 304 respiratory motion traces are performed. The experimental results demonstrate that the EKF-SVR algorithm successfully reduces the prediction error of the LCM-EKF, and outperforms the model-free ANN and SVR algorithms in terms of prediction accuracy across lookahead lengths of 192, 384, and 576 ms.

Multi-step prediction of physiological tremor for robotics applications.

The performance of surgical robotic devices in real-time mainly depends on phase-delay in sensors and filtering process. A phase delay of 16-20 ms is unavoidable in these robotics procedures due to the presence of hardware low pass filter in sensors and pre-filtering required in later stages of cancellation. To overcome this phase delay, we employ multi-step prediction with band limited multiple Fourier linear combiner (BMFLC) and Autoregressive (AR) methods. Results show that the overall accuracy is improved by 60% for tremor estimation compared to single-step prediction methods in the presence of phase delay. Experimental results with the proposed methods for 1-DOF tremor estimation highlight the improvement.

Effect of bacteriophage supplementation on the growth performance, nutrient digestibility, blood characteristics, and fecal microbial shedding in growing pigs.

A total of 144 ((Duroc×Yorkshire)×Landrace)) pigs with an average initial BW of 28.85±0.63 kg were used in this 6-wk growth trial. Pigs were randomly allotted to 1 of 4 treatments in a completely random block design. Each dietary treatment consisted of 9 replicate pens, with 4 pigs per replicate. Dietary treatments included: i) NC (basal diet), ii) PC (NC+apramycin 0.5 g/kg), iii) BPT1 (NC+bacteriophage 0.25 g/kg) and iv) BPT2 (NC+bacteriophage 0.5 g/kg). The inclusion of antibiotics and bacteriophages did not affect the (p>0.05) ADG, ADFI and G:F compared with the basal diet. Dietary antibiotics and bacteriophages supplementation led to a higher (p<0.05) DM digestibility than the NC treatment. Pigs fed the bacteriophage supplemented diet increased (p<0.05) the N digestibility compared with those fed NC treatment. Supplementation of antibiotics led to a higher (p<0.05) energy digestibility than the NC treatment. No difference (p>0.05) was observed in the RBC, WBC, lymphocyte concentration and fecal moisture among treatments. Pigs fed PC and BPT2 treatments reduced (p<0.05) the E. coli concentration compared with those fed NC treatment. The inclusion of BPT2 treatment led to a higher (p<0.05) lactobacillus concentration compared with NC and PC treatment. Dietary antibiotic and bacteriophage supplementation reduced (p<0.05) the Salmonella concentration compared with NC treatment. In conclusion, our study suggested that bacteriophage at the level of 0.5 g/kg could be used as an antibiotics alternative for growing pigs.

Effect of Medium-chain Triglyceride (MCT) on Growth Performance, Nutrient Digestibility, Blood Characteristics in Weanling Pigs.

One hundred and twenty weanling pigs in experiment 1 (Exp. 1) (6.91±0.99 kg; 21 d of age) and Exp. 2 (10.20±1.09 kg; 28 d of age) were used in two 42-d and 35-d experiments to evaluate the effect of medium-chain-triglyceride (MCT) on growth performance, apparent total tract digestibility (ATTD) of nutrients and blood profile. In both of Exp. 1 and Exp. 2, the same dietary treatments were utilized as follows : i) negative control (NC), ii) positive control (PC), NC+antibiotics (40 mg/kg Tiamulin, 110 mg/kg Tylosin, and 10 mg/kg Enramycin, iii) MCT3, NC+0.32% (phase 1, 2 and 3) MCT, and iv) MCT5, NC+0.55% (phase 1), 0.32% (phase 2 and 3) MCT. In Exp. 1, the pigs fed MCT5 diets had higher (p<0.05) ADG compared to NC treatment during the first 2 wk. From d 15 to 28, the ATTD of energy was improved (p<0.05) by MCT3 compared to the PC treatment. No effect has been observed on the blood profiles [red blood cell (RBC), white blood cell (WBC), immunoglobulin-G (IgG), lymphocyte concentration] measured in this study. In Exp. 2, the ADG were increased (p<0.05) by the MCT5 treatment than the PC treatment from d 0 to 14. Pigs fed PC treatment diet had lower ADFI (p<0.05) and better FCR (p<0.05) than NC treatment, whereas no differences were shown between MCT treatments and NC or PC treatment from d 15 to 35 and overall phase. The ATTD of DM and nitrogen were improved (p<0.05) by the effect of MCT5 related to the NC and PC treatment at the end of 2nd and 5th wk. The pigs fed MCT3 had higher (p<0.05) energy digestibility than PC treatment. No effects were seen in the blood profiles we measured (WBC, RBC, lymphocyte and immunoglobulin-G). In conclusion, the addition of MCT in the weanling pigs diet can improve the ADG and digestibility during the earlier period (first 2 wks), but had little effect on the blood characteristics.

Evaluation of the effect of low dietary fermentable carbohydrate content on growth performance, nutrient digestibility, blood characteristics, and meat quality in finishing pigs.

A total of 96 pigs (49.23±3.20 kg) were used in an 11 wk growth trial to evaluate the effect of fermentable carbohydrate (FC) content on growth performance, apparent total tract digestibility (ATTD) of nutrient, blood profile, and meat quality. The dietary treatments were: i) negative control (NC), basal diet, ii) positive control (PC), NC+antibiotics (positive control diet with 5 ppm flavomycin), iii) PCL, PC-13% lower FC, and iv) NCL, NC-13% lower FC. The growth performance (average daily gain, average daily feed intake, and gain/feed) didn't differ among treatments through the whole experiment. These pigs fed the PCL diet had the greater (p<0.05) apparent total tract digestibility (ATTD) of dry matter than those from PC and NC treatment at the end of the experiment. No differences were observed in white blood cell (WBC), red blood cell (RBC), and lymphocyte concentration among different treatments. After the feeding period, meat samples were collected from the pigs at slaughter. The pigs in NCL and PCL treatments had greater (p<0.05) backfat thickness and lower lean percentage. The color value of loin was higher (p<0.05) in NCL treatment compared to PCL treatment. Also, the NCL treatment had higher (p<0.05) marbling value than PC treatment. The drip loss was depressed by PCL and NCL treatment comapared to NC treatments. The water holding capacity (WHC) was higher (p<0.05) in NC and PCL treatment. In conclusion, the low FC can improve digestibility and meat quality of finishing pigs.

The evaluation of soybean meals from 3 major soybean-producing countries on productive performance and feeding value of pig diets.

This study was conducted to evaluate 1) the effects of soybean meal (SBM) from 3 major SBM-producing countries (United States, Brazil, and India) on the growth performance, nutrient digestibility, and meat quality of growing-finishing pigs and 2) the feeding value of the evaluated SBM as a feedstuff for growing-finishing pigs. Soybean meal representative of each country was purchased on the open market. A total of 144 barrows with the average BW of 23.77 (SD = 1.52 kg) were allotted to 3 dietary treatments with 12 replicate pens per treatment and 4 pigs per pen. The US SBM used in this trial had greater CP and total AA contents, greater KOH protein solubility, and less crude fiber than SBM from either Brazil or India. Diets were formulated to be isolysinic and isocaloric. Pigs fed diets containing US SBM were heavier (P < 0.05) than pigs fed diets containing Brazilian or Indian SBM at 12 and 18 wk. Pigs fed diets containing US SBM had greater (P < 0.05) ADG and G:F throughout the overall period when compared with pigs fed SBM produced in Brazil or India. The DM and N digestibility were greater for US SBM (P < 0.05) than Brazilian and India SBM at 6, 12, and 18 wk. Pigs were slaughtered at the end of 18 wk, and no differences were observed on meat quality (backfat thickness, LM area, pH, meat color, water holding capacity, and drip loss) among the treatments, except lean percentages were less and backfat thickness was greater in pigs fed Brazilian and Indian SBM than US SBM. The cost per kilogram of BW gain of the experimental diet containing US SBM was less than that of diets containing Brazilian or Indian SBM, but it would depend on the relative prices of each SBM. Based on the results of the current experiment, the productivity and feeding value of US SBM seems to be greater than the SBM produced in Brazil and India.

Tumour epithelial vimentin expression and outcome of pancreatic ductal adenocarcinomas.

PURPOSE: Tumour epithelial vimentin expression is a marker of mesenchymal differentiation and may be a useful marker of carcinomas with more aggressive behaviour. The aim of this study was to determine the extent and prognostic significance of vimentin expression in pancreatic ductal adenocarcinomas. METHODS: Vimentin expression was detected by immunohistochemistry on tissue microarrays of surgically resected pancreatic ductal adenocarcinomas from 387 patients. The percentage of vimentin-immunolabelled neoplastic cells was correlated with outcome and with clinico-pathological factors using the Kaplan-Meier method and Cox multivariate survival models. RESULTS: In all, 45% of primary pancreatic adenocarcinomas contained neoplastic cells that expressed vimentin, and in 27.5% of the cancers >10% of cells expressed vimentin. Vimentin expression was correlated with poor histological differentiation. By both uni- and multivariate survival analysis, neoplastic vimentin expression (P<0.01, HR 1.52, 95% confidence interval 1.14-2.04) was an indicator of a shorter postsurgical survival independent of other clinico-pathological variables. CONCLUSION: The presence of vimentin-expressing tumour epithelial cells in surgically resected pancreatic adenocarcinomas independently predicted a shorter postsurgical survival.

Real-time prediction of respiratory motion based on a local dynamic model in an augmented space.

Motion-adaptive radiotherapy aims to deliver ablative radiation dose to the tumor target with minimal normal tissue exposure, by accounting for real-time target movement. In practice, prediction is usually necessary to compensate for system latency induced by measurement, communication and control. This work focuses on predicting respiratory motion, which is most dominant for thoracic and abdominal tumors. We develop and investigate the use of a local dynamic model in an augmented space, motivated by the observation that respiratory movement exhibits a locally circular pattern in a plane augmented with a delayed axis. By including the angular velocity as part of the system state, the proposed dynamic model effectively captures the natural evolution of respiratory motion. The first-order extended Kalman filter is used to propagate and update the state estimate. The target location is predicted by evaluating the local dynamic model equations at the required prediction length. This method is complementary to existing work in that (1) the local circular motion model characterizes 'turning', overcoming the limitation of linear motion models; (2) it uses a natural state representation including the local angular velocity and updates the state estimate systematically, offering explicit physical interpretations; (3) it relies on a parametric model and is much less data-satiate than the typical adaptive semiparametric or nonparametric method. We tested the performance of the proposed method with ten RPM traces, using the normalized root mean squared difference between the predicted value and the retrospective observation as the error metric. Its performance was compared with predictors based on the linear model, the interacting multiple linear models and the kernel density estimator for various combinations of prediction lengths and observation rates. The local dynamic model based approach provides the best performance for short to medium prediction lengths under relatively low observation rate. Sensitivity analysis indicates its robustness toward the choice of parameters. Its simplicity, robustness and low computation cost makes the proposed local dynamic model an attractive tool for real-time prediction with system latencies below 0.4 s.

Characterization of ΔNp73 expression and regulation in gastric and esophageal tumors.

p73 is a member of the p53 protein family. Although the tumor suppressor function of p53 is clearly defined, the role of p73 in tumorigenesis is still a matter of debate. A complex pattern of expression of p73 isoforms makes it difficult to unambiguously interpret the experimental results. Previously, we along with others have found that the N-terminally truncated isoform of p73, ΔNp73, has potent anti-apoptotic and oncogenic properties in vitro and in vivo. In this study, we analyzed, for the first time, the regulation of ΔNp73 in a large number of gastric, gastroesophageal junction and esophageal tumors. We found that expression of ΔNp73 mRNA and protein is increased in these neoplasms. Furthermore, the upregulation of the ΔNp73 protein is significantly associated with poor patient survival. Oncogenic properties of ΔNp73 were further confirmed by finding that ΔNp73 facilitates anchorage-independent growth of gastric epithelial cells in soft agar. As little is currently known about the regulation of ΔNp73 transcription, we investigated the alternative p73 gene promoter that mediates the ΔNp73 expression. Analyzing the ΔNp73 promoter in silico as well as by using chromatin immunoprecipitation, site-directed mutagenesis and deletion analyses, we identified the evolutionary conserved region within the ΔNp73 promoter that contains binding sites for HIC1 (hypermethylated in cancer) protein. We found that HIC1 negatively regulates ΔNp73 transcription in mucosal epithelial cells. This leads to a decrease in ΔNp73 protein levels and may normally control the oncogenic potential of the ΔNp73 isoform.

Congenital stapedial suprastructure fixation with normal footplate mobility: case report.

OBJECTIVE: We report a case of bilateral conductive hearing loss caused by stapedial suprastructure fixation with normal footplate mobility. CASE REPORT: A 50-year-old woman had suffered hearing loss in both ears since childhood. Exploratory tympanotomy revealed immobility of the stapes due to a bony bridge between the stapedial suprastructure and the fallopian canal. The incus was missing, while the malleus handle was minimally deformed. The mobility of the stapes footplate was normal. Post-operatively, the hearing in the right ear improved both subjectively and audiographically, while that in the left ear did not improve because of footplate subluxation during surgery. CONCLUSION: This is a rare case of congenital stapedial suprastructure fixation with normal footplate mobility. In this patient, development of the second branchial arch was arrested. When performing exploratory tympanotomy for stapedial fixation, one must keep in mind that normal footplate mobility is possible.

A dominant hereditary ossicular anomaly: bilateral incus anomaly and stapes fixation.

OBJECTIVE: We report three generations of one family suffering from bilateral conductive hearing loss due to a congenital anomaly of the incus and stapes fixation. CASE REPORT: All three female patients presented with similar symptoms and findings of hearing impairment since birth. Their computed tomography findings were the same. An abnormally shaped incus, fixed stapes and hanging tympanic portion of the facial nerve were seen at surgery. Stapedotomy could not be performed because the hanging facial nerve blocked the operating field. CONCLUSION: Although several cases of familial ossicular anomaly have been reported, this is the first report of an incus anomaly and stapes fixation combined with a facial nerve anomaly.