Rituximab, bendamustine, and lenalidomide in patients with aggressive B cell lymphoma not eligible for high-dose chemotherapy or anthracycline-based therapy: phase I results of the SAKK 38/08 trial

This phase I trial was designed to develop a new effective and well-tolerated regimen for patients with aggressive B cell lymphoma not eligible for front-line anthracycline-based chemotherapy or aggressive second-line treatment strategies. The combination of rituximab (375 mg/m(2) on day 1), bendamustine (70 mg/m(2) on days 1 and 2), and lenalidomide was tested with a dose escalation of lenalidomide at three dose levels (10, 15, or 20 mg/day) using a 3 + 3 design. Courses were repeated every 4 weeks. The recommended dose was defined as one level below the dose level identifying ≥2/6 patients with a dose-limiting toxicity (DLT) during the first cycle. Thirteen patients were eligible for analysis. Median age was 77 years. WHO performance status was 0 or 1 in 12 patients. The Charlson Comorbidity Index showed relevant comorbidities in all patients. Two DLTs occurred at the second dose level (15 mg/day) within the first cycle: one patient had prolonged grade 3 neutropenia, and one patient experienced grade 4 cardiac adverse event (myocardial infarction). Additional grade 3 and 4 toxicities were as follows: neutropenia (31 %), thrombocytopenia (23 %), cardiac toxicity (31 %), fatigue (15 %), and rash (15 %). The dose of lenalidomide of 10 mg/day was recommended for a subsequent phase II in combination with rituximab 375 mg/m(2) on day 1 and bendamustine 70 mg/m(2) on days 1 and 2.

A modified calculation of ankle-brachial pressure index is far more sensitive in the detection of peripheral arterial disease

BACKGROUND: Ankle-brachial pressure index (ABI) is a simple, inexpensive, and useful tool in the detection of peripheral arterial occlusive disease (PAD). The current guidelines published by the American Heart Association define ABI as the quotient of the higher of the systolic blood pressures (SBPs) of the two ankle arteries of that limb (either the anterior tibial artery or the posterior tibial artery) and the higher of the two brachial SBPs of the upper limbs. We hypothesized that considering the lower of the two ankle arterial SBPs of a side as the numerator and the higher of the brachial SBPs as the denominator would increase its diagnostic yield. METHODS: The former method of eliciting ABI was termed as high ankle pressure (HAP) and the latter low ankle pressure (LAP). ABI was assessed in 216 subjects and calculated according to the HAP and the LAP method. ABI findings were confirmed by arterial duplex ultrasonography. A significant arterial stenosis was assumed if ABI was <0.9. RESULTS: LAP had a sensitivity of 0.89 and a specificity of 0.93. The HAP method had a sensitivity of 0.68 and a specificity of 0.99. McNemar's test to compare the results of both methods demonstrated a two-tailed P < .0001, indicating a highly significant difference between both measurement methods. CONCLUSIONS: LAP is the superior method of calculating ABI to identify PAD. This result is of great interest for epidemiologic studies applying ABI measurements to detect PAD and assessing patients' cardiovascular risk.

Compositional protein analysis of high density lipoproteins in hypercholesterolemia by shotgun LC-MS/MS and probabilistic peptide scoring

A protein of a biological sample is usually quantified by immunological techniques based on antibodies. Mass spectrometry offers alternative approaches that are not dependent on antibody affinity and avidity, protein isoforms, quaternary structures, or steric hindrance of antibody-antigen recognition in case of multiprotein complexes. One approach is the use of stable isotope-labeled internal standards; another is the direct exploitation of mass spectrometric signals recorded by LC-MS/MS analysis of protein digests. Here we assessed the peptide match score summation index based on probabilistic peptide scores calculated by the PHENYX protein identification engine for absolute protein quantification in accordance with the protein abundance index as proposed by Mann and co-workers (Rappsilber, J., Ryder, U., Lamond, A. I., and Mann, M. (2002) Large-scale proteomic analysis of the human spliceosome. Genome Res. 12, 1231-1245). Using synthetic protein mixtures, we demonstrated that this approach works well, although proteins can have different response factors. Applied to high density lipoproteins (HDLs), this new approach compared favorably to alternative protein quantitation methods like UV detection of protein peaks separated by capillary electrophoresis or quantitation of protein spots on SDS-PAGE. We compared the protein composition of a well defined HDL density class isolated from plasma of seven hypercholesterolemia subjects having low or high HDL cholesterol with HDL from nine normolipidemia subjects. The quantitative protein patterns distinguished individuals according to the corresponding concentration and distribution of cholesterol from serum lipid measurements of the same samples and revealed that hypercholesterolemia in unrelated individuals is the result of different deficiencies. The presented approach is complementary to HDL lipid analysis; does not rely on complicated sample treatment, e.g. chemical reactions, or antibodies; and can be used for projective clinical studies of larger patient groups.

Applicability and dosimetric impact of ultrasound-based preplanning in high-dose-rate brachytherapy of prostate cancer

BACKGROUND AND PURPOSE: Analyses of permanent brachytherapy seed implants of the prostate have demonstrated that the use of a preplan may lead to a considerable decrease of dosimetric implant quality. The authors aimed to determine whether the same drawbacks of preplanning also apply to high-dose-rate (HDR) brachytherapy. PATIENTS AND METHODS: 15 patients who underwent two separate HDR brachytherapy implants in addition to external-beam radiation therapy for advanced prostate cancer were analyzed. A pretherapeutic transrectal ultrasound was performed in all patients to generate a preplan for the first brachytherapy implant. For the second brachytherapy, a subset of patients were treated by preplans based on the ultrasound from the first brachytherapy implant. Preplans were compared with the respective postplans assessing the following parameters: coverage index, minimum target dose, homogeneity index, and dose exposure of organs at risk. The prostate geometries (volume, width, height, length) were compared as well. RESULTS: At the first brachytherapy, the matching between the preplan and actual implant geometry was sufficient in 47% of the patients, and the preplan could be applied. The dosimetric implant quality decreased considerably: the mean coverage differed by -0.11, the mean minimum target dose by -0.15, the mean homogeneity index by -0.09. The exposure of organs at risk was not substantially altered. At the second brachytherapy, all patients could be treated by the preplan; the differences between the implant quality parameters were less pronounced. The changes of prostate geometry between preplans and postplans were considerable, the differences in volume ranging from -8.0 to 13.8 cm(3) and in dimensions (width, height, length) from -1.1 to 1.0 cm. CONCLUSION: Preplanning in HDR brachytherapy of the prostate is associated with a substantial decrease of dosimetric implant quality, when the preplan is based on a pretherapeutic ultrasound. The implant quality is less impaired in subsequent implants of fractionated brachytherapy.

Perioperative fluid management: comparison of high, medium and low fluid volume on tissue oxygen pressure in the small bowel and colon

BACKGROUND AND OBJECTIVE: Insufficient blood flow and oxygenation in the intestinal tract is associated with increased incidence of postoperative complications after bowel surgery. High fluid volume administration may prevent occult regional hypoperfusion and intestinal tissue hypoxia. We tested the hypothesis that high intraoperative fluid volume administration increases intestinal wall tissue oxygen pressure during laparotomy. METHODS: In all, 27 pigs were anaesthetized, ventilated and randomly assigned to one of the three treatment groups (n = 9 in each) receiving low (3 mL kg-1 h-1), medium (7 mL kg-1 h-1) or high (20 mL kg-1 h-1) fluid volume treatment with lactated Ringer's solution. All animals received 30% and 100% inspired oxygen in random order. Cardiac index was measured with thermodilution and tissue oxygen pressure with a micro-oximetry system in the jejunum and colon wall and subcutaneous tissue. RESULTS: Groups receiving low and medium fluid volume treatment had similar systemic haemodynamics. The high fluid volume group had significantly higher mean arterial pressure, cardiac index and subcutaneous tissue oxygenation. Tissue oxygen pressures in the jejunum and colon were comparable in all three groups. CONCLUSIONS: The three different fluid volume regimens tested did not affect tissue oxygen pressure in the jejunum and colon, suggesting efficient autoregulation of intestinal blood flow in healthy subjects undergoing uncomplicated abdominal surgery.

Simulation in training: one-year experience using an efficiency index to assess interventional radiology fellow training status

PURPOSE: To compare objective fellow and expert efficiency indices for an interventional radiology renal artery stenosis skill set with the use of a high-fidelity simulator. MATERIALS AND METHODS: The Mentice VIST simulator was used for three different renal artery stenosis simulations of varying difficulty, which were used to grade performance. Fellows' indices at three intervals throughout 1 year were compared to expert baseline performance. Seventy-four simulated procedures were performed, 63 of which were captured as audiovisual recordings. Three levels of fellow experience were analyzed: 1, 6, and 12 months of dedicated interventional radiology fellowship. The recordings were compiled on a computer workstation and analyzed. Distinct measurable events in the procedures were identified with task analysis, and data regarding efficiency were extracted. Total scores were calculated as the product of procedure time, fluoroscopy time, tools, and contrast agent volume. The lowest scores, which reflected efficient use of tools, radiation, and time, were considered to indicate proficiency. Subjective analysis of participants' procedural errors was not included in this analysis. RESULTS: Fellows' mean scores diminished from 1 month to 12 months (42,960 at 1 month, 18,726 at 6 months, and 9,636 at 12 months). The experts' mean score was 4,660. In addition, the range of variance in score diminished with increasing experience (from a range of 5,940-120,156 at 1 month to 2,436-85,272 at 6 months and 2,160-32,400 at 12 months). Expert scores ranged from 1,450 to 10,800. CONCLUSIONS: Objective efficiency indices for simulated procedures can demonstrate scores directly comparable to the level of clinical experience.

Testing the GlaaS algorithm for dose measurements on low- and high-energy photon beams using an amorphous silicon portal imager

The GLAaS algorithm for pretreatment intensity modulation radiation therapy absolute dose verification based on the use of amorphous silicon detectors, as described in Nicolini et al. [G. Nicolini, A. Fogliata, E. Vanetti, A. Clivio, and L. Cozzi, Med. Phys. 33, 2839-2851 (2006)], was tested under a variety of experimental conditions to investigate its robustness, the possibility of using it in different clinics and its performance. GLAaS was therefore tested on a low-energy Varian Clinac (6 MV) equipped with an amorphous silicon Portal Vision PV-aS500 with electronic readout IAS2 and on a high-energy Clinac (6 and 15 MV) equipped with a PV-aS1000 and IAS3 electronics. Tests were performed for three calibration conditions: A: adding buildup on the top of the cassette such that SDD-SSD = d(max) and comparing measurements with corresponding doses computed at d(max), B: without adding any buildup on the top of the cassette and considering only the intrinsic water-equivalent thickness of the electronic portal imaging devices device (0.8 cm), and C: without adding any buildup on the top of the cassette but comparing measurements against doses computed at d(max). This procedure is similar to that usually applied when in vivo dosimetry is performed with solid state diodes without sufficient buildup material. Quantitatively, the gamma index (gamma), as described by Low et al. [D. A. Low, W. B. Harms, S. Mutic, and J. A. Purdy, Med. Phys. 25, 656-660 (1998)], was assessed. The gamma index was computed for a distance to agreement (DTA) of 3 mm. The dose difference deltaD was considered as 2%, 3%, and 4%. As a measure of the quality of results, the fraction of field area with gamma larger than 1 (%FA) was scored. Results over a set of 50 test samples (including fields from head and neck, breast, prostate, anal canal, and brain cases) and from the long-term routine usage, demonstrated the robustness and stability of GLAaS. In general, the mean values of %FA remain below 3% for deltaD equal or larger than 3%, while they are slightly larger for deltaD = 2% with %FA in the range from 3% to 8%. Since its introduction in routine practice, 1453 fields have been verified with GLAaS at the authors' institute (6 MV beam). Using a DTA of 3 mm and a deltaD of 4% the authors obtained %FA = 0.9 +/- 1.1 for the entire data set while, stratifying according to the dose calculation algorithm, they observed: %FA = 0.7 +/- 0.9 for fields computed with the analytical anisotropic algorithm and %FA = 2.4 +/- 1.3 for pencil-beam based fields with a statistically significant difference between the two groups. If data are stratified according to field splitting, they observed %FA = 0.8 +/- 1.0 for split fields and 1.0 +/- 1.2 for nonsplit fields without any significant difference.

Entropy and bispectral index for assessment of sedation, analgesia and the effects of unpleasant stimuli in critically ill patients: an observational study

INTRODUCTION: Sedative and analgesic drugs are frequently used in critically ill patients. Their overuse may prolong mechanical ventilation and length of stay in the intensive care unit. Guidelines recommend use of sedation protocols that include sedation scores and trials of sedation cessation to minimize drug use. We evaluated processed electroencephalography (response and state entropy and bispectral index) as an adjunct to monitoring effects of commonly used sedative and analgesic drugs and intratracheal suctioning. METHODS: Electrodes for monitoring bispectral index and entropy were placed on the foreheads of 44 critically ill patients requiring mechanical ventilation and who previously had no brain dysfunction. Sedation was targeted individually using the Ramsay Sedation Scale, recorded every 2 hours or more frequently. Use of and indications for sedative and analgesic drugs and intratracheal suctioning were recorded manually and using a camera. At the end of the study, processed electroencephalographical and haemodynamic variables collected before and after each drug application and tracheal suctioning were analyzed. Ramsay score was used for comparison with processed electroencephalography when assessed within 15 minutes of an intervention. RESULTS: The indications for boli of sedative drugs exhibited statistically significant, albeit clinically irrelevant, differences in terms of their association with processed electroencephalographical parameters. Electroencephalographical variables decreased significantly after bolus, but a specific pattern in electroencephalographical variables before drug administration was not identified. The same was true for opiate administration. At both 30 minutes and 2 minutes before intratracheal suctioning, there was no difference in electroencephalographical or clinical signs in patients who had or had not received drugs 10 minutes before suctioning. Among patients who received drugs, electroencephalographical parameters returned to baseline more rapidly. In those cases in which Ramsay score was assessed before the event, processed electroencephalography exhibited high variation. CONCLUSIONS: Unpleasant or painful stimuli and sedative and analgesic drugs are associated with significant changes in processed electroencephalographical parameters. However, clinical indications for drug administration were not reflected by these electroencephalographical parameters, and barely by sedation level before drug administration or tracheal suction. This precludes incorporation of entropy and bispectral index as target variables for sedation and analgesia protocols in critically ill patients.

Lifestyle factors and colorectal cancer risk (1): systematic review and meta-analysis of associations with body mass index

OBJECTIVE: Excess body weight, defined by body mass index (BMI), may increase the risk of colorectal cancer. As a prerequisite to the determination of lifestyle attributable risks, we undertook a systematic review and meta-analysis of prospective observational studies to quantify colorectal cancer risk associated with increased BMI and explore for differences by gender, sub-site and study characteristics. METHOD: We searched MEDLINE and EMBASE (to December 2007), and other sources, selecting reports based on strict inclusion criteria. Random-effects meta-analyses and meta-regressions of study-specific incremental estimates were performed to determine the risk ratio (RR) and 95% confidence intervals (CIs) associated with a 5 kg/m(2) increase in BMI. RESULTS: We analysed 29 datasets from 28 articles, including 67,361 incident cases. Higher BMI was associated with colon (RR 1.24, 95% CIs: 1.20-1.28) and rectal (1.09, 1.05-1.14) cancers in men, and with colon cancer (1.09, 1.04-1.12) in women. Associations were stronger in men than in women for colon (P < 0.001) and rectal (P = 0.005) cancers. Associations were generally consistent across geographic populations. Study characteristics and adjustments accounted for only moderate variations of associations. CONCLUSION: Increasing BMI is associated with a modest increased risk of developing colon and rectal cancers, but this modest risk may translate to large attributable proportions in high-prevalence obese populations. Inter-gender differences point to potentially important mechanistic differences, which merit further research.

Index of Complexity, Outcome and Need scored on plaster and digital models

The aim of this study was to compare standard plaster models with their digital counterparts for the applicability of the Index of Complexity, Outcome, and Need (ICON). Generated study models of 30 randomly selected patients: 30 pre- (T(0)) and 30 post- (T(1)) treatment. Two examiners, calibrated in the ICON, scored the digital and plaster models. The overall ICON scores were evaluated for reliability and reproducibility using kappa statistics and reliability coefficients. The values for reliability of the total and weighted ICON scores were generally high for the T(0) sample (range 0.83-0.95) but less high for the T(1) sample (range 0.55-0.85). Differences in total ICON score between plaster and digital models resulted in mostly statistically insignificant values (P values ranging from 0.07 to 0.19), except for observer 1 in the T(1) sample. No statistically different values were found for the total ICON score on either plaster or digital models. ICON scores performed on computer-based models appear to be as accurate and reliable as ICON scores on plaster models.

Oscillometric measurement of ankle-brachial index in patients with suspected peripheral disease: comparison with Doppler method

QUESTION UNDER STUDY: Purpose was to validate accuracy and reliability of automated oscillometric ankle-brachial (ABI) measurement prospectively against the current gold standard of Doppler-assisted ABI determination. METHODS: Oscillometric ABI was measured in 50 consecutive patients with peripheral arterial disease (n = 100 limbs, mean age 65 +/- 6 years, 31 men, 19 diabetics) after both high and low ABI had been determined conventionally by Doppler under standardised conditions. Correlation was assessed by linear regression and Pearson product moment correlation. Degree of inter-modality agreement was quantified by use of Bland and Altman method. RESULTS: Oscillometry was performed significantly faster than Doppler-assisted ABI (3.9 +/- 1.3 vs 11.4 +/- 3.8 minutes, P <0.001). Mean readings were 0.62 +/- 0.25, 0.70 +/- 0.22 and 0.63 +/- 0.39 for low, high and oscillometric ABI, respectively. Correlation between oscillometry and Doppler ABI was good overall (r = 0.76 for both low and high ABI) and excellent in oligo-symptomatic, non-diabetic patients (r = 0.81; 0.07 +/- 0.23); it was, however, limited in diabetic patients and in patients with critical limb ischaemia. In general, oscillometric ABI readings were slightly higher (+0.06), but linear regression analysis showed that correlation was sustained over the whole range of measurements. CONCLUSIONS: Results of automated oscillometric ABI determination correlated well with Doppler-assisted measurements and could be obtained in shorter time. Agreement was particularly high in oligo-symptomatic non-diabetic patients.

Auditory event-related potentials, bispectral index, and entropy for the discrimination of different levels of sedation in intensive care unit patients

BACKGROUND: Sedation protocols, including the use of sedation scales and regular sedation stops, help to reduce the length of mechanical ventilation and intensive care unit stay. Because clinical assessment of depth of sedation is labor-intensive, performed only intermittently, and interferes with sedation and sleep, processed electrophysiological signals from the brain have gained interest as surrogates. We hypothesized that auditory event-related potentials (ERPs), Bispectral Index (BIS), and Entropy can discriminate among clinically relevant sedation levels. METHODS: We studied 10 patients after elective thoracic or abdominal surgery with general anesthesia. Electroencephalogram, BIS, state entropy (SE), response entropy (RE), and ERPs were recorded immediately after surgery in the intensive care unit at Richmond Agitation-Sedation Scale (RASS) scores of -5 (very deep sedation), -4 (deep sedation), -3 to -1 (moderate sedation), and 0 (awake) during decreasing target-controlled sedation with propofol and remifentanil. Reference measurements for baseline levels were performed before or several days after the operation. RESULTS: At baseline, RASS -5, RASS -4, RASS -3 to -1, and RASS 0, BIS was 94 [4] (median, IQR), 47 [15], 68 [9], 75 [10], and 88 [6]; SE was 87 [3], 46 [10], 60 [22], 74 [21], and 87 [5]; and RE was 97 [4], 48 [9], 71 [25], 81 [18], and 96 [3], respectively (all P < 0.05, Friedman Test). Both BIS and Entropy had high variabilities. When ERP N100 amplitudes were considered alone, ERPs did not differ significantly among sedation levels. Nevertheless, discriminant ERP analysis including two parameters of principal component analysis revealed a prediction probability PK value of 0.89 for differentiating deep sedation, moderate sedation, and awake state. The corresponding PK for RE, SE, and BIS was 0.88, 0.89, and 0.85, respectively. CONCLUSIONS: Neither ERPs nor BIS or Entropy can replace clinical sedation assessment with standard scoring systems. Discrimination among very deep, deep to moderate, and no sedation after general anesthesia can be provided by ERPs and processed electroencephalograms, with similar P(K)s. The high inter- and intraindividual variability of Entropy and BIS precludes defining a target range of values to predict the sedation level in critically ill patients using these parameters. The variability of ERPs is unknown.

Late Holocene summer temperatures in the central Andes reconstructed from the sediments of high-elevatin Laguna Chepical, Chile (32° S)

High-resolution reconstructions of climate variability that cover the past millennia are necessary to improve the understanding of natural and anthropogenic climate change across the globe. Although numerous records are available for the mid- and high-latitudes of the Northern Hemisphere, global assessments are still compromised by the scarcity of data from the Southern Hemisphere. This is particularly the case for the tropical and subtropical areas. In addition, high elevation sites in the South American Andes may provide insight into the vertical structure of climate change in the mid-troposphere. This study presents a 3000 yr-long austral summer (November to February) temperature reconstruction derived from the 210Pb- and 14C-dated organic sediments of Laguna Chepical (32°16' S, 70°30' W, 3050 m a.s.l.), a high-elevation glacial lake in the subtropical Andes of central Chile. Scanning reflectance spectroscopy in the visible light range provided the spectral index R570/R630, which reflects the clay mineral content in lake sediments. For the calibration period (AD 1901–2006), the R570/R630 data were regressed against monthly meteorological reanalysis data, showing that this proxy was strongly and significantly correlated with mean summer (NDJF) temperatures (R3 yr = −0.63, padj = 0.01). This calibration model was used to make a quantitative temperature reconstruction back to 1000 BC. The reconstruction (with a model error RMSEPboot of 0.33 °C) shows that the warmest decades of the past 3000 yr occurred during the calibration period. The 19th century (end of the Little Ice Age (LIA)) was cool. The prominent warmth reconstructed for the 18th century, which was also observed in other records from this area, seems systematic for subtropical and southern South America but remains difficult to explain. Except for this warm period, the LIA was generally characterized by cool summers. Back to AD 1400, the results from this study compare remarkably well to low altitude records from the Chilean Central Valley and southern South America. However, the reconstruction from Laguna Chepical does not show a warm Medieval Climate Anomaly during the 12–13th century, which is consistent with records from tropical South America. The Chepical record also indicates substantial cooling prior to 800 BC. This coincides with well-known regional as well as global glacier advances which have been attributed to a grand solar minimum. This study thus provides insight into the climatic drivers and temperature patterns in a region for which currently very few data are available. It also shows that since ca. AD 1400, long-term temperature patterns were generally similar at low and high altitudes in central Chile.

Operative treatment of congenital hip osteoarthritis with high hip luxation (Crowe type IV)

OBJECTIVE The aim of the therapy is mechanical and functional stabilization of high dislocated hips with dysplasia coxarthrosis using total hip arthroplasty (THA). INDICATIONS Developmental dysplasia of the hip (DDH) in adults, symptomatic dysplasia coxarthrosis, high hip dislocation according to Crowe type III/IV, and symptomatic leg length inequality. CONTRAINDICATIONS Cerebrospinal dysfunction, muscular dystrophy, apparent disturbance of bone metabolism, acute or chronic infections, and immunocompromised patients. SURGICAL TECHNIQUE With the patient in a lateral decubitus position an incision is made between the anterior border of the gluteus maximus muscle and the posterior border of the gluteus medius muscle (Gibson interval). Identification of the sciatic nerve to protect the nerve from traction disorders by visual control. After performing trochanter flip osteotomy, preparation of the true actetabulum if possible. Implantation of the reinforcement ring, preparation of the femur and if necessary for mobilization, resection until the trochanter minor. Test repositioning under control of the sciatic nerve. Finally, refixation of the trochanteric crest. POSTOPERATIVE MANAGEMENT During hospital stay, intensive mobilization of the hip joint using a continuous passive motion machine with maximum flexion of 70°. No active abduction and passive adduction over the body midline. Maximum weight bearing 10-15 kg for 8 weeks, subsequently, first clinical and radiographic follow-up and deep venous thrombosis prophylaxis until full weight bearing. RESULTS From 1995 to 2012, 28 THAs of a Crow type IV high hip-dislocation were performed in our institute. Until now 14 patients have been analyzed during a follow-up of 8 years in 2012. Mid-term results showed an improvement of the postoperative clinical score (Merle d'Aubigné score) in 86 % of patients. Good to excellent results were obtained in 79 % of cases. Long-term results are not yet available. In one case an iatrogenic neuropraxia of the sciatic nerve was observed and after trauma a redislocation of the arthroplasty appeared in another case. In 2 cases an infection of the THA appeared 8 and 15 months after index surgery. No pseudoarthrosis of the trochanter or aseptic loosening was noticed.