TP53 as a Biomarker in Head and Neck Squamous Cell Carcinoma

Currently, there are no molecular biomarkers that guide treatment decisions for patients with head and neck squamous cell carcinoma (HNSCC). Several retrospective studies have evaluated TP53 in HNSCC, and results have suggested that specific mutations are associated with poor outcome. However, there exists heterogeneity among these studies in the site and stage of disease of the patients reviewed, the treatments rendered, and methods of evaluating TP53 mutation. Thus, it remains unclear as to which patients and in which clinical settings TP53 mutation is most useful in predicting treatment failure. In the current study, we reviewed the records of a cohort of patients with advanced, resectable HNSCC who received surgery and post-operative radiation (PORT) and had DNA isolated from fresh tumor tissue obtained at the time of surgery. TP53 mutations were identified using Sanger sequencing of exons 2-11 and the associated splice regions of the TP53 gene. We have found that the group of patients with either non-disruptive or disruptive TP53 mutations had decreased overall survival, disease-free survival, and an increased rate of distant metastasis. When examined as an independent factor, disruptive mutation was strongly associated with the development of distant metastasis. As a second aim of this project, we performed a pilot study examining the utility of the AmpliChip® p53 test as a practical method for TP53 sequencing in the clinical setting. AmpliChip® testing and Sanger sequencing was performed on a separate cohort of patients with HNSCC. Our study demonstrated the ablity of the AmpliChip® to call TP53 mutation from a single formalin-fixed paraffin-embedded slide. The results from AmpliChip® testing were identical with the Sanger method in 11 of 19 cases, with a higher rate of mutation calls using the AmpliChip® test. TP53 mutation is a potential prognostic biomarker among patients with advanced, resectable HNSCC treated with surgery and PORT. Whether this subgroup of patients could benefit from the addition of concurrent or induction chemotherapy remains to be evaluated in prospective clinical trials. Our pilot study of the p53 AmpliChip® suggests this could be a practical and reliable method of TP53 analysis in the clinical setting.

Investigation of bacteremia induced by removal of orthodontic mini-implants.

The aim of this study was to investigate potential occurrence of bacteremia in orthodontic patients after removal of miniscrews.The study group comprised 30 healthy subjects (17 males, 13 females) with a mean age of 24.1 years treated with self-ligating fixed appliances and mini-implant anchorage. Two 20 ml venous blood samples were obtained prior to and 30-60 seconds after miniscrew explantation following an aseptic technique. Blood culturing in aerobic and anaerobic conditions was carried out by means of the BACTEC blood culture analyzer. Microbiological analysis showed that none of the pre- and post-operative samples exhibited detectable bacteremia. Future research should be focused on determining the collective bacteremic effect of a sequence of orthodontic procedures including miniscrew placement or removal, typically performed during a single treatment session.

X-ray image calibration and its application to clinical orthopedics.

X-ray imaging is one of the most commonly used medical imaging modality. Albeit X-ray radiographs provide important clinical information for diagnosis, planning and post-operative follow-up, the challenging interpretation due to its 2D projection characteristics and the unknown magnification factor constrain the full benefit of X-ray imaging. In order to overcome these drawbacks, we proposed here an easy-to-use X-ray calibration object and developed an optimization method to robustly find correspondences between the 3D fiducials of the calibration object and their 2D projections. In this work we present all the details of this outlined concept. Moreover, we demonstrate the potential of using such a method to precisely extract information from calibrated X-ray radiographs for two different orthopedic applications: post-operative acetabular cup implant orientation measurement and 3D vertebral body displacement measurement during preoperative traction tests. In the first application, we have achieved a clinically acceptable accuracy of below 1° for both anteversion and inclination angles, where in the second application an average displacement of 8.06±3.71 mm was measured. The results of both applications indicate the importance of using X-ray calibration in the clinical routine.

A comparison of apical root resorption after orthodontic treatment with surgical exposure and traction of maxillary impacted canines versus that without impactions.

SUMMARY BACKGROUND/OBJECTIVES Orthodontic management of maxillary canine impaction (MCI), including forced eruption, may result in significant root resorption; however, the association between MCI and orthodontically induced root resorption (OIRR) is not yet sufficiently established. The purpose of this retrospective cohort study was to comparatively evaluate the severity of OIRR of maxillary incisors in orthodontically treated patients with MCI. Additionally, impaction characteristics were associated with OIRR severity. SUBJECTS AND METHODS The sample comprised 48 patients undergoing fixed-appliance treatment-24 with unilateral/bilateral MCI and 24 matched controls without impaction. OIRR was calculated using pre- and post-operative panoramic tomograms. The orientation of eruption path, height, sector location, and follicle/tooth ratio of the impacted canine were also recorded. Mann-Whitney U-test and univariate and multivariate linear mixed models were used to test for the associations of interest. RESULTS Maxillary central left incisor underwent more OIRR in the impaction group (mean difference = 0.58mm, P = 0.04). Overall, the impaction group had 0.38mm more OIRR compared to the control (95% confidence interval, CI: 0.03, 0.74; P = 0.04). However, multivariate analysis demonstrated no difference in the amount of OIRR between impaction and non-impaction groups overall. A positive association between OIRR and initial root length was observed (95% CI: 0.08, 0.27; P < 0.001). The severity of canine impaction was not found to be a significant predictor of OIRR. LIMITATIONS This study was a retrospective study and used panoramic tomograms for OIRR measurements. CONCLUSIONS This study indicates that MCI is a weak OIRR predictor. Interpretation of the results needs caution due to the observational nature of the present study.

Antioxidant supplementation attenuates oxidative stress in patients undergoing coronary artery bypass graft surgery.

Ischemia-reperfusion has been reported to be associated with augmented oxidative stress in the course of surgery, which might be causally involved in the onset of atrial fibrillation (AF), the most common arrhythmia after cardiac surgery. We hypothesized that supplementation of antioxidants and n-3 polyunsaturated fatty acids (n-3 PUFAs) might lower the incidence of AF following coronary artery bypass graft (CABG) surgery. In the present study, by monitoring oxidative stress in the course of CABG surgery, we analyzed the efficacy of vitamins (ascorbic acid and α-tocopherol) and/or n-3 PUFAs (eicosapentaenoic acid and docosahexaenoic acid). Subjects (n = 75) were divided into 4 subgroups: control, vitamins, n-3 PUFAs, and a combination of vitamins and n-3 PUFAs. Fluorescent techniques were used to measure the antioxidative capacity, i.e. ability to inhibit oxidation. Total peroxides, endogenous peroxidase activity, and antibodies against oxidized LDL (oLAb) were used as serum oxidative stress biomarkers. Post-operative increase in oxidative stress was associated with the consumption of antioxidants and a simultaneous onset of AF. This was confirmed through an increased peroxide level and a decreased oLAb titer in control and n-3 PUFAs groups, indicating the binding of antibodies to oxidative modified epitopes. In both subgroups that were supplemented with vitamins, total peroxides decreased, and the maintenance of a constant IgG antibody titer was facilitated. However, treatment with vitamins or n-3 PUFAs was inefficient with respect to AF onset and its duration. We conclude that the administration of vitamins attenuates post-operative oxidative stress in the course of CABG surgery.

Early renal failure after domino hepatic transplantation using the liver from a compound heterozygous patient with primary hyperoxaluria.

BACKGROUND To cover the shortage of cadaveric organs, new approaches to expand the donor pool are needed. Here we report on a case of domino liver transplantation (DLT) using an organ harvested from a compound heterozygous patient with primary hyperoxaluria (PHO), who underwent combined liver and kidney transplantation. The DLT recipient developed early renal failure with oxaluria. The time to the progression to oxalosis with renal failure in such situations is unknown, but, based on animal data, we hypothesize that calcineurin inhibitors may play a detrimental role. METHODS A cadaveric liver and kidney transplantation was performed in a 52-year-old male with PHO. His liver was used for a 64-year-old patient with a non-resectable, but limited cholangiocarcinoma. RESULTS While the course of the PHO donor was uneventful, in the DLT recipient early post-operative, dialysis-dependent renal failure with hyperoxaluria developed. Histology of a kidney biopsy revealed massive calcium oxalate crystal deposition as the leading aetiological cause. CONCLUSIONS DLT using PHO organs for marginal recipients represents a possible therapeutic approach regarding graft function of the liver. However, it may negatively alter the renal outcome of the recipient in an unpredictable manner, especially with concomitant use of cyclosporin. Therefore, we suggest that, although DLT should be promoted, PHO organs are better excluded from such procedures.

Temperature Prediction Model for Bone Drilling Based on Density Distribution and In Vivo Experiments for Minimally Invasive Robotic Cochlear Implantation

Surgical robots have been proposed ex vivo to drill precise holes in the temporal bone for minimally invasive cochlear implantation. The main risk of the procedure is damage of the facial nerve due to mechanical interaction or due to temperature elevation during the drilling process. To evaluate the thermal risk of the drilling process, a simplified model is proposed which aims to enable an assessment of risk posed to the facial nerve for a given set of constant process parameters for different mastoid bone densities. The model uses the bone density distribution along the drilling trajectory in the mastoid bone to calculate a time dependent heat production function at the tip of the drill bit. Using a time dependent moving point source Green's function, the heat equation can be solved at a certain point in space so that the resulting temperatures can be calculated over time. The model was calibrated and initially verified with in vivo temperature data. The data was collected in minimally invasive robotic drilling of 12 holes in four different sheep. The sheep were anesthetized and the temperature elevations were measured with a thermocouple which was inserted in a previously drilled hole next to the planned drilling trajectory. Bone density distributions were extracted from pre-operative CT data by averaging Hounsfield values over the drill bit diameter. Post-operative [Formula: see text]CT data was used to verify the drilling accuracy of the trajectories. The comparison of measured and calculated temperatures shows a very good match for both heating and cooling phases. The average prediction error of the maximum temperature was less than 0.7 °C and the average root mean square error was approximately 0.5 °C. To analyze potential thermal damage, the model was used to calculate temperature profiles and cumulative equivalent minutes at 43 °C at a minimal distance to the facial nerve. For the selected drilling parameters, temperature elevation profiles and cumulative equivalent minutes suggest that thermal elevation of this minimally invasive cochlear implantation surgery may pose a risk to the facial nerve, especially in sclerotic or high density mastoid bones. Optimized drilling parameters need to be evaluated and the model could be used for future risk evaluation.

2D-3D Reconstruction-Based Planning of Total Hip Arthroplasty

This chapter proposed a personalized X-ray reconstruction-based planning and post-operative treatment evaluation framework called iJoint for advancing modern Total Hip Arthroplasty (THA). Based on a mobile X-ray image calibration phantom and a unique 2D-3D reconstruction technique, iJoint can generate patient-specific models of hip joint by non-rigidly matching statistical shape models to the X-ray radiographs. Such a reconstruction enables a true 3D planning and treatment evaluation of hip arthroplasty from just 2D X-ray radiographs whose acquisition is part of the standard diagnostic and treatment loop. As part of the system, a 3D model-based planning environment provides surgeons with hip arthroplasty related parameters such as implant type, size, position, offset and leg length equalization. With this newly developed system, we are able to provide true 3D solutions for computer assisted planning of THA using only 2D X-ray radiographs, which is not only innovative but also cost-effective.

Comparison of 2.5D and 3D Quantification of Femoral Head Coverage in Normal Control Subjects and Patients with Hip Dysplasia.

Hip dysplasia is characterized by insufficient femoral head coverage (FHC). Quantification of FHC is of importance as the underlying goal of the surgery to treat hip dysplasia is to restore a normal acetabular morphology and thereby to improve FHC. Unlike a pure 2D X-ray radiograph-based measurement method or a pure 3D CT-based measurement method, previously we presented a 2.5D method to quantify FHC from a single anteriorposterior (AP) pelvic radiograph. In this study, we first quantified and compared 3D FHC between a normal control group and a patient group using a CT-based measurement method. Taking the CT-based 3D measurements of FHC as the gold standard, we further quantified the bias, precision and correlation between the 2.5D measurements and the 3D measurements on both the control group and the patient group. Based on digitally reconstructed radiographs (DRRs), we investigated the influence of the pelvic tilt on the 2.5D measurements of FHC. The intraclass correlation coefficients (ICCs) for absolute agreement was used to quantify interobserver reliability and intraobserver reproducibility of the 2.5D measurement technique. The Pearson correlation coefficient, r, was used to determine the strength of the linear association between the 2.5D and the 3D measurements. Student's t-test was used to determine whether the differences between different measurements were statistically significant. Our experimental results demonstrated that both the interobserver reliability and the intraobserver reproducibility of the 2.5D measurement technique were very good (ICCs > 0.8). Regression analysis indicated that the correlation was very strong between the 2.5D and the 3D measurements (r = 0.89, p < 0.001). Student's t-test showed that there were no statistically significant differences between the 2.5D and the 3D measurements of FHC on the patient group (p > 0.05). The results of this study provided convincing evidence demonstrating the validity of the 2.5D measurements of FHC from a single AP pelvic radiograph and proved that it could serve as a surrogate for 3D CT-based measurements. Thus it may be possible to use this method to avoid a CT scan for the purpose of estimating 3D FHC in diagnosis and post-operative treatment evaluation of patients with hip dysplasia.

The Rendez-vous technique for treatment of caesarean scar defects: a novel combined endoscopic approach.

BACKGROUND A caesarean scar defect is a late complication of caesarean birth with a wide range of prevalence between 56 and 84 % depending on which diagnostic tool and which definition is used [1]. The referred symptoms which include postmenstrual spotting and infertility are fortunately rare. Moreover, severe complications such as caesarean scar pregnancy and uterine rupture in the following pregnancy may occur. Given the increasing incidence of caesarean births, the potential morbidity associated with caesarean scars is likely to become more important. Recently, a few repair techniques were described in the literature including the hysteroscopic resection of scarred tissue or the laparoscopic repair with or without robotic assistance [2, 3]. METHODS Between June 2009 and February 2014, 21 women with caesarean scar defects were operated with the Rendez-vous technique, a minimally invasive surgery combining the laparoscopic and hysteroscopic approach. Data were retrospectively collected. The indications for this surgery included secondary infertility, previous caesarean scar pregnancy, recurrent miscarriage and postmenstrual spotting. Prior to operation, a transvaginal ultrasound was performed to examine the uterine wall defect. RESULTS The patient characteristics are provided in Table 1. In all cases, the operation was successfully completed laparoscopically. The median operation time was 125 min. One case was complicated by recurrence of the scar defect 6 weeks after the operation. No other intra- or post-operative complications were observed, and the median in-patient stay was 3 days. CONCLUSIONS The benefits of the technique include the feasibility and safety of the procedure, the "Halloween sign" (Fig. 1) which indicates the exact extent and localization of the scar defect and the immediate assessment of repair through the hysteroscopy at the end of the surgery. However, before further studies evaluate the efficacy of this method, the routine repair of caesarean scar defects cannot be recommended. A video of the technique is presented.

Bilateral deep brain stimulation: the placement of the second electrode is not necessarily less accurate than that of the first one.

BACKGROUND Deep brain stimulation (DBS) is recognized as an effective treatment for movement disorders. We recently changed our technique, limiting the number of brain penetrations to three per side. OBJECTIVES The first aim was to evaluate the electrode precision on both sides of surgery since we implemented this surgical technique. The second aim was to analyse whether or not the electrode placement was improved with microrecording and macrostimulation. METHODS We retrospectively reviewed operation protocols and MRIs of 30 patients who underwent bilateral DBS. For microrecording and macrostimulation, we used three parallel channels of the 'Ben Gun' centred on the MRI-planned target. Pre- and post-operative MRIs were merged. The distance between the planned target and the centre of the implanted electrode artefact was measured. RESULTS There was no significant difference in targeting precision on both sides of surgery. There was more intra-operative adjustment of the second electrode positioning based on microrecording and macrostimulation, which allowed to significantly approach the MRI-planned target on the medial-lateral axis. CONCLUSION There was more electrode adjustment needed on the second side, possibly in relation with brain shift. We thus suggest performing a single central track with electrophysiological and clinical assessment, with multidirectional exploration on demand for suboptimal clinical responses.

Comparison of patients in three different rehabilitation settings after knee or hip arthroplasty: a natural observational, prospective study.

BACKGROUND Patients after primary hip or knee replacement surgery can benefit from postoperative treatment in terms of improvement of independence in ambulation, transfers, range of motion and muscle strength. After discharge from hospital, patients are referred to different treatment destination and modalities: intensive inpatient rehabilitation (IR), cure (medically prescribed stay at a convalescence center), or ambulatory treatment (AT) at home. The purpose of this study was to 1) measure functional health (primary outcome) and function relevant factors in patients with hip or knee arthroplasty and to compare them in relation to three postoperative management strategies: AT, Cure and IR and 2) compare the post-operative changes in patient's health status (between preoperative and the 6 month follow-up) for three rehabilitation settings. METHODS Natural observational, prospective two-center study with follow-up. Sociodemographic data and functional mobility tests, Timed Up and Go (TUG) and Iowa Level of Assistance Scale (ILOAS) of 201 patients were analysed before arthroplasty and at the end of acute hospital stay (mean duration of stay: 9.7 days +/- 3.9). Changes in health state were measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) before and 6 months after arthroplasty. RESULTS Compared to patients referred for IR and Cure, patients referred for AT were significantly younger and less comorbid. Patients admitted to IR had the highest functional disability before arthroplasty. Before rehabilitation, mean TUG was 40.0 s in the IR group, 33.9 s in the Cure group, and 27.5 s in the AT group, and corresponding mean ILOAS was 16.0, 13.0 and 12.2 (50.0 = worst). At the 6 months follow-up, the corresponding effect sizes of the WOMAC global score were 1.32, 1.87, and 1.51 (>0 means improvement). CONCLUSIONS Age, comorbidity and functional disability are associated with referral for intensive inpatient rehabilitation after hip or knee arthroplasty and partly affect health changes after rehabilitation.

The muscarinic antagonists scopolamine and atropine are competitive antagonists at 5-HT3 receptors

Scopolamine is a high affinity muscarinic antagonist that is used for the prevention of post-operative nausea and vomiting. 5-HT3 receptor antagonists are used for the same purpose and are structurally related to scopolamine. To examine whether 5-HT3 receptors are affected by scopolamine we examined the effects of this drug on the electrophysiological and ligand binding properties of 5-HT3A receptors expressed in Xenopus oocytes and HEK293 cells, respectively. 5-HT3 receptor-responses were reversibly inhibited by scopolamine with an IC50 of 2.09 μM. Competitive antagonism was shown by Schild plot (pA2 = 5.02) and by competition with the 5-HT3 receptor antagonists [3H]granisetron (Ki = 6.76 µM) and G-FL (Ki = 4.90 µM). The related molecule, atropine, similarly inhibited 5-HT evoked responses in oocytes with an IC50 of 1.74 µM, and competed with G-FL with a Ki of 7.94 µM. The reverse experiment revealed that granisetron also competitively bound to muscarinic receptors (Ki = 6.5 µM). In behavioural studies scopolamine is used to block muscarinic receptors and induce a cognitive deficit, and centrally administered concentrations can exceed the IC50 values found here. It is therefore possible that 5-HT3 receptors are also inhibited. Studies that utilise higher concentrations of scopolamine should be mindful of these potential off-target effects.

Risk of second primary tumors following treatment of non-small cell lung cancer

Background. The rise in survival rates along with more detailed follow-up using sophisticated imaging studies among non-small lung cancer (NSCLC) patients has led to an increased risk of second primary tumors (SPT) among these cases. Population and hospital based studies of lung cancer patients treated between 1974 and 1996 have found an increasing risk over time for the development of all cancers following treatment of non-small cell lung cancer (NSCLC). During this time the primary modalities for treatment were surgery alone, radiation alone, surgery and post-operative radiation therapy, or combinations of chemotherapy and radiation (sequentially or concurrently). There is limited information in the literature about the impact of treatment modalities on the development of second primary tumors in these patients. ^ Purpose. To investigate the impact of treatment modalities on the risk of second primary tumors in patients receiving treatment with curative intent for non-metastatic (Stage I–III) non-small cell lung cancer (NSCLC). ^ Methods. The hospital records of 1,095 NSCLC patients who were diagnosed between 1980–2001 and received treatment with curative intent at M.D. Anderson Cancer Center with surgery alone, radiation alone (with a minimum total radiation dose of at least 45Gy), surgery and post-operative radiation therapy, radiation therapy in combination with chemotherapy or surgery in combination with chemotherapy and radiation were retrospectively reviewed. A second primary malignancy was be defined as any tumor histologically different from the initial cancer, or of another anatomic location, or a tumor of the same location and histology as the initial tumor having an interval between cancers of at least five years. Only primary tumors occurring after treatment for NSCLC will qualified as second primary tumors for this study. ^ Results. The incidence of second primary tumor was 3.3%/year and the rate increased over time following treatment. The type of NSCLC treatment was not found to have a striking effect upon SPT development. Increased rates were observed in the radiation only and chemotherapy plus radiation treatment groups; but, these increases did not exceed expected random variation. Higher radiation treatment dose, patient age and weight loss prior to index NSCLC treatment were associated with higher SPT development. ^

Risk factors for spinal surgical site infection

Background. Surgical site infections (SSI) are one of the most common nosocomial infections in the United States. This study was conducted following an increase in the rate of SSI following spinal procedures at the study hospital. ^ Methods. This study examined patient and hospital associated risk factors for SSI using existing data on patients who had spinal surgery performed at the study hospital between December 2003 and August 2005. There were 59 patients with SSI identified as cases; controls were randomly selected from patients who had spinal procedures performed at the study hospital during the study period, but did not develop infection. Of the 245 original records reviewed, 5% were missing more than half the variables and were eliminated from the data set. A total of 234 patients were included in the final analysis, representing 55 cases and 179 controls. Multivariable analysis was conducted using logistic regression to control for confounding variables. ^ Results. Three variables were found to be significant risk factors for SSI in the study population: presence of comorbidities (odds ratio 3.15, 95% confidence interval 1.20 to 8.26), cut time above the population median of 100 minutes (odds ratio 2.98, 95% confidence interval 1.12 to 5.49), and use of iodine only for preoperative skin antisepsis (odds ratio 0.16, 95% confidence interval 0.06 to 0.45). Several risk factors of specific concern to the study hospital, such as operating room, hospital staff involved in the procedures and workers' compensation status, were not shown to be statistically significant. In addition, multiple factors that have been identified in prior studies, such as method of hair removal, smoking status, or incontinence, were not shown to be statistically significant in this population. ^ Conclusions. This study confirms that increased cut time is a risk for post-operative infection. Use of iodine only was found to decrease risk of infection; further study is recommended in a population with higher usage of chlorhexadine gluconate. Presence of comorbidities at the time of surgery was also found to be a risk factor for infection; however, specific comorbidities were not studied. ^