[Early assessment of the risk of later implantloosening using Roentgen Sterophotogrammetric Analysis (RSA)]. / Früherkennung des Risikos der späteren Implantatlockerung mittels der Röntgen Stereophotogrammetrischen Analyse (RSA).

BACKGROUND: Aseptic implant loosening is the most common cause of implant revisions in total hip and total knee arthroplasty. Roentgen Stereophotogrammetric Analysis (RSA) represents the current gold standard for the in-vivo assessment of implant fixation. PRESENT SITUATION: Long-term clinical trials have shown that continuous implant migration within the first two postoperative years correlates strongly with a later aseptic loosening. Thus, the implant migration measured with RSA can be regarded as a reliable surrogate marker for later implant loosening. Over the past 40 years, RSA has been continuously further developed, and the model-based RSA approach has reduced the effort involved since markers attached to implant are no longer needed. PERSPECTIVES: The RSA method is gaining importance in the certification process of new orthopaedic implants-for example, the Dutch Orthopedic Society has recommended phased-introduction and RSA studies for new hip implants. Furthermore, in the context of the new EU Medical Device Regulation (MDR), which took effect in May 2017, RSA gained relevance for investigating clinically unproven implants. Critics who associate MDR with hindering innovation can be countered in that the RSA method provides a predictive assessment of implant fixation after only two years of follow-up, which is significantly shorter than standard long-term clinical trials.

[Bearing selection in total hip arthroplasty]. / Wahl der richtigen Gleitpaarung in der Hüftendoprothetik.

Different bearing materials are available in total hip arthroplasty and it's the surgeon who has the choice between hard-on-soft, hard-on-hard and alternative materials. Ideally, the material selection should rely on evidence-based data regarding the wear performance, the incidence of revision surgery and other potential bearing-associated risk factors for the corresponding combinations of materials in the individual patient. While there are high-quality studies available for some materials, adequate data is lacking for other materials. Therefore, the current article aims to provide bearing selection criteria for the surgeon and to review the current literature regarding different combinations of bearing materials in total hip arthroplasty.

Fixation of the shorter cementless GTS™ stem: biomechanical comparison between a conventional and an innovative implant design.

INTRODUCTION: Conventional cementless total hip arthroplasty already shows very good clinical results. Nevertheless, implant revision is often accompanied by massive bone loss. The new shorter GTS™ stem has been introduced to conserve femoral bone stock. However, no long-term clinical results were available for this implant. A biomechanical comparison of the GTS™ stem with the clinically well-established CLS(®) stem was therefore preformed to investigate the targeted stem philosophy. MATERIALS AND METHODS: Four GTS™ stems and four CLS(®) stems were implanted in a standardized manner in eight synthetic femurs. A high-precision measuring device was used to determine micromotions of the stem and bone during different load applications. Calculation of relative micromotions at the bone-implant interface allowed the rotational implant stability and the bending behavior of the stem to be determined. RESULTS: Lowest relative micromotions were detected near the lesser trochanter within the proximal part of both stems. Maximum relative micromotions were measured near the distal tip of the stems, indicating a proximal fixation of both stems. For the varus-valgus-torque application, a comparable stem bending behavior was shown for both stems. CONCLUSION: Both stems seem to provide a comparable and adequate primary stability. The shortened GTS™ design has a comparable rotational stability and bone-implant flexibility compared to a conventional stem. This study demonstrates that the CLS(®) stem and the GTS™ stem exhibit similar biomechanical behavior. However, a clinical confirmation of these experimental results is still required.

Pro-apoptotic Sorafenib signaling in murine hepatocytes depends on malignancy and is associated with PUMA expression in vitro and in vivo.

The multi-kinase inhibitor Sorafenib increases the survival of patients with advanced hepatocellular carcinoma (HCC). Current data suggest that Sorafenib inhibits cellular proliferation and angiogenesis and promotes apoptosis. However, the underlying pro-apoptotic molecular mechanisms are incompletely understood. Here we compared the pro-apoptotic and anti-proliferative properties of Sorafenib in murine hepatoma cells and syngeneic healthy hepatocytes in vitro and in animal models of HCC and liver regeneration in vivo. In vitro, we demonstrate that cell cycle activity and expression of anti-apoptotic Bcl-2 like proteins are similarly downregulated by Sorafenib in Hepa1-6 hepatoma cells and in syngeneic primary hepatocytes. However, Sorafenib-mediated activation of caspase-3 and induction of apoptosis were exclusively found in hepatoma cells, but not in matching primary hepatocytes. We validated these findings in vivo by applying an isograft HCC transplantation model and partial hepatectomy (PH) in C57BL/6 mice. Sorafenib treatment activated caspase-3 and thus apoptosis selectively in small tumor foci that originated from implanted Hepa1-6 cells but not in surrounding healthy hepatocytes. Similarly, Sorafenib did not induce apoptosis after PH. However, Sorafenib treatment transiently inhibited cell cycle progression and resulted in mitotic catastrophe and enhanced non-apoptotic liver injury during regeneration. Importantly, Sorafenib-mediated apoptosis in hepatoma cells was associated with the expression of p53-upregulated-modulator-of-apoptosis (PUMA). In contrast, regenerating livers after PH revealed downregulation of PUMA and were completely protected from Sorafenib-mediated apoptosis. We conclude that Sorafenib induces apoptosis selectively in hepatoma cells but not in healthy hepatocytes and can additionally increase non-apoptotic hepatocyte injury in the regenerating liver.

[Metal ion concentrations in patients with metal-metal bearings in prostheses]. / Metallkonzentrationen bei Patienten mit Metall-Metall-Gleitpaarungs-Prothese.

Increased wear leads to elevated systemic and local metal ion concentrations for patients treated with metal-on-metal bearings. The local metal ion content in the close environment of the joint replacement (e.g. joint aspirate or tissue) is several times higher compared to the systemic metal content (e.g. in blood or serum). As a result of increased metal ion levels, local and systemic effects, such as osteolysis, pseudotumors, sensitization or in rare cases toxicity may occur. Although the definition of a specific threshold to define clinical problems is difficult due to a lack of sensitivity, the systemic metal concentration is frequently measured clinically. Currently a threshold for cobalt and chromium between 4 µg/l and 7 µg/l is under debate. Very high levels (≥ 20 µg/l) or a steady increase over time should be a warning sign; however, metal ion levels should not be interpreted as a single diagnostic tool but rather in the entire context of the clinical, radiological and cross-sectional imaging, metal artefact reduction sequence (MARS) magnetic resonance imaging (MRI), ultrasound and computed tomography (CT) findings.

[Principles of tribological analysis of endoprostheses]. / Grundlagen zur tribologischen Analyse von Endoprothesen.

For the tribological characterization of artificial joints, various experimental methods are currently available. However, the in vitro test conditions applied are only comparable in a limited way and transferability to the in vivo situation is also restricted. This is due to the different wear simulation concepts used and partly insufficient simulation of clinical worst case situations. In the present paper current scientific methods and procedures for tribological testing of artificial joints are presented. In addition, the biological effects of wear products are described enabling clinicians to challenge tribological studies and to facilitate specific interpretation of scientific results taking the clinical situation into account.

What's next? Alternative materials for articulation in total joint replacement.

The use of an artificial joint is always related to a certain amount of wear. Its biological effects, e.g., the osteolysis potential, are a function of the bulk material as well as its debris. Following comprehensive experiences with polyethylene (PE) wear, material science is tracking two ways to minimize the risk of a particle-induced aseptic implant loosening: (i) reduction of the PE debris by a low-wearing articulation partner; and (ii) replacement of the PE by other materials. Therefore, new ceramics (e.g., ZTA, Si(3)N(4)), as well as coatings (e.g., TiN, "diamond-like" carbon) and modifications of a bulk metal (e.g., oxidizes zirconium) or cushion bearings (polyurethane, hydrogels), are currently available for total joint replacements or have been used for pre-clinical testing. This review gives a brief overview and evaluates the potential of those that have recently been published in literature.

Fertility and sexual function following orchiectomy and 2 cycles of chemotherapy for stage I high risk nonseminomatous germ cell cancer.

PURPOSE: We investigate fertility and sexual function in patients following orchiectomy and adjuvant cisplatin based chemotherapy for high risk, stage I nonseminomatous germ cell tumor of the testis. MATERIALS AND METHODS: Between 1985 and 1994, 59 patients with stage I nonseminomatous germ cell tumor and poor prognostic factors were treated with 2 cycles of cisplatin, vinblastine and bleomycin, or bleomycin, etoposide and cisplatin after orchiectomy. At least 32 months following treatment all patients were contacted and asked to complete a questionnaire regarding fertility and sexual activity, and to volunteer for a semen and hormonal analysis. RESULTS: Of the 59 patients 49 (83%) completed the questionnaire. Before chemotherapy 18 (37%) patients had fathered children, 6 (12%) were involuntarily childless and none had a major sexual dysfunction. After treatment 11 (22%) patients fathered children, and 5 (10%) were involuntarily childless, with 4 involuntarily childless before chemotherapy. There were no significant alterations in sexual function. Semen analysis in 27 patients was normal in 23, and revealed mild oligospermia in 2 and azoospermia in 2. In 18 patients with hormone analysis median values for luteinizing hormone and free testosterone were normal but median value for follicle-stimulating hormone was slightly increased. CONCLUSIONS: Two cycles of cisplatin based adjuvant chemotherapy do not seem to affect adversely fertility or sexual activity.

Risk adapted management with adjuvant chemotherapy in patients with high risk clinical stage i nonseminomatous germ cell tumor.

PURPOSE: We propose that patients with high risk, clinical stage I nonseminomatous germ cell tumors receive 2 cycles of chemotherapy initially, instead of undergoing surgery or observation. MATERIALS AND METHODS: A total of 59 patients with high risk, clinical stage I nonseminomatous germ cell tumor received risk adapted adjuvant chemotherapy. Until June 1987, 20 patients were treated with 2 courses of adjuvant cisplatin, vinblastine and bleomycin at 3-week intervals. After June 1987 another 39 patients were treated with 2 cycles of bleomycin, etoposide and cisplatin. RESULTS: Long-term results with this treatment strategy have been excellent with limited morbidity. CONCLUSIONS: Adjuvant chemotherapy may be of particular value in patients with compromised followup.

Long-term results following adjuvant chemotherapy in patients with clinical stage I testicular nonseminomatous malignant germ cell tumors with high risk factors.

PURPOSE: We determine the efficacy and safety of 2 cycles of adjuvant chemotherapy after orchiectomy in patients with high risk clinical stage I nonseminomatous germ cell tumor of the testis as an alternative to retroperitoneal lymphadenectomy or watchful waiting. MATERIALS AND METHODS: A total of 60 consecutive patients with clinical stage I nonseminomatous germ cell tumor of the testis and 1 or more risk factors were entered into this prospective study. Criteria for high risk were embryonal cell carcinoma, tumor invasion of blood or lymph vessels, or tumor stage pT2 or greater. Chemotherapy consisted of 2 cycles of cisplatin, vinblastine and bleomycin or bleomycin, etoposide and cisplatin. RESULTS: Of the 60 patients 1 refused chemotherapy and 1 was lost to followup 1.5 years after treatment. The remaining 58 patients have been followed for a median of 93 months (range 32 to 146). World Health Organization grade 4 toxicity was observed in 9 of the 116 chemotherapy cycles, and consisted mainly of transient neutropenia and thrombocytopenia. No significant long-term sequelae were detected. There was 1 relapse after 22 months in a patient with adult teratoma in the ipsilateral region of the iliac vessels who remained disease-free 85 months after surgical excision of the lesion. Another patient had a seminoma in the contralateral testicle with interaortocaval lymph node metastases 7.5 years after adjuvant chemotherapy. The remaining 56 men are without relapse or contralateral tumor to date. CONCLUSIONS: We recommend adjuvant chemotherapy as an efficient therapeutic alternative to retroperitoneal lymphadenectomy for high risk nonseminomatous germ cell tumor of the testis.

Adjuvant cisplatin chemotherapy following cystectomy for bladder cancer: results of a prospective randomized trial.

Between April 1984 and May 1989, 77 eligible patients with invasive, nonmetastatic (stage M0) transitional cell carcinoma of the bladder were stratified after radical cystectomy and pelvic lymph node dissection on the basis of nodal status (stage pN0 versus pN1-2) and were randomly assigned to either observation or postoperative cisplatin chemotherapy (3 courses of 90 mg./m.2 cisplatin given for 3 consecutive days at monthly intervals). Patient eligibility included a creatinine clearance of greater than 60 ml. per minute. There were 40 eligible patients in the control group (median age 61 years) and 37 in the cisplatin group (median age 64 years). In regard to postoperative tumor stage and nodal status, there was no statistical difference between the 2 patient groups. In the cisplatin group 21 patients received the full dose, 9 required dose reduction and 7 refused treatment. Median followup was 5 years 9 months (range 3 to 8 years). Survival analysis showed no significant difference (log rank p = 0.65) between the 40 patients in the control group and the 37 in the cisplatin group. The survival rate at 5 years was 54% (95% confidence interval 39 to 69%) in the control group and 57% (95% confidence interval 40 to 74%) in the treatment group. Patients with cancer confined to the bladder wall (stage pT3a or less) had a 5-year overall survival rate of 70% and those with tumor growth in the perivesical fat or into the prostate (stages pT3b plus pT4a) had a 5-year overall survival rate of 40%. This difference in survival between the low stage subgroup (stages pT3a or less) and the high stage subgroup (pT3b plus pT4a) is highly significant (p = 0.0043). However, no difference between the controls and the cisplatin group was found within either the low or high stage subgroups. The reasons for failing to show a survival benefit from adjuvant high dose cisplatin monotherapy after radical cystectomy are discussed.

Invasion depth is the most important prognostic factor for transitional-cell carcinoma in a prospective trial of radical cystectomy and adjuvant chemotherapy.

The aim of this prospective study was to examine the prognostic pathomorphological factors in urothelial cancer of the urinary bladder. Clinical and morphological variables were evaluated by univariate and multivariate analysis in 70 patients with invasive transitional-cell carcinoma of the bladder (pTI-pT4a). The patients were treated according to a prospective program consisting of radical cystectomy and pelvic-node dissection, either alone or followed by adjuvant cisplatinum chemotherapy. Nodal status was pN0 in 89% of the patients. The median follow-up time was 5.75 years and the 5-year survival was 58%. Among the morphologic variables, deep invasion of the bladder wall and squamous differentiation indicated a poorer prognosis. Differentiation grade, pattern of growth (infiltrating versus expanding), angioinvasive growth, glandular differentiation and concomitant prostate carcinoma (pT1) were not significative factors for survival. By contrast, a significant reduction in mortality rate was found in patients with concomitant carcinoma in situ. Multivariate analysis confirmed that depth of invasion is an independent prognostic factor of outcome. The results confirm the primary importance of tumor stage in the prediction of survival after radical cystectomy.

Adjuvant chemotherapy after orchiectomy in high-risk patients with clinical stage I non-seminomatous testicular cancer.

In patients with clinical stage I non-seminomatous germ cell tumor the relapse rate seen after orchiectomy alone is approximately 30%. If retroperitoneal lymph node dissection is adopted the relapse rate in patients with histologically negative retroperitoneal nodes is reduced to approximately 10%. Nevertheless, follow-up is still mandatory and 70-80% of clinical stage I patients undergo unnecessary surgery. Metastases and relapses are mostly seen in patients with histological evidence of vascular invasion, growth beyond the testicular capsule and/or embryonal carcinoma in the primary tumor. We conducted a prospective trial of two cycles of cisplatin-based adjuvant chemotherapy for 43 patients with clinical stage I non-seminomatous germ cell tumors and at least one of these risk factors (vascular invasion n = 5, pT > 1 n = 21, embryonal carcinoma n = 42). After a median follow-up of 42 months (12-82 months) 40/41 patients (97.5%) who received the planned chemotherapy remain relapse-free. One patient had surgical excision of a mature teratoma in the ipsilateral iliac region 26 months after orchiectomy and is now disease-free without further treatment after 25+ months. No life-threatening toxicity from chemotherapy was encountered. Two patients who refused the chemotherapy relapsed. In patients with high-risk clinical stage I non-seminomatous testicular cancer two cycles of adjuvant chemotherapy are highly effective in preventing relapses and may be used as an alternative to a 'wait and watch' program or retroperitoneal lymph node dissection, particularly in patients with a compromised follow-up.

Sequential double labelling with different fluorescent dyes coupled to dextran amines as a tool to estimate the accuracy of tracer application and of regeneration.

We present a technique to estimate the accuracy of a given application procedure for neuronal tracers. In a second series of animals we used this technique for the estimation of successful regeneration of peripheral nerves. Dextran amine coupled to rhodamine was applied to the cut trochlar nerve in Xenopus tadpoles. To assess the accuracy of tracer application, experiments were done in which a second dye, dextran amine coupled to fluorescein, was applied after 1 day proximal to the first dye. More then 90% of all trochlear motoneurons were doubly labelled after this procedure. Their total numbers were not significantly different from numbers obtained after single labelling with HRP in a comparable age group. To assess success of regeneration after 5 and 8 days, the second application of fluorescein dextran amine was distal to the first application side. Statistically significant differences suggest incomplete regeneration of many neurons. After 42 days the numbers of singly and doubly labelled motoneurons was in the same proportion as before regeneration. This suggests that about 90% of the surviving motoneurons had successfully regenerated back to the periphery.

Development of the amphibian oculomotor complex: evidences for migration of oculomotor motoneurons across the midline.

The development of the oculomotor nucleus in five species of salamanders and one anuran species was investigated with tracing techniques. The data presented support the hypothesis that oculomotor motoneurons innervating the superior rectus muscle migrate across the midline. In the salamander Pleurodeles waltl, only ipsilateral oculomotor motoneurons are labeled in early development. Later, these neurons extend dendrites toward the contralateral side into the ventral tegmental neuropil, after which there is displacement of their nuclei (neuronal somata) across the midline. Cell bodies can be observed directly at the midline. In adult Salamandra salamandra, motoneurons innervating the superior rectus muscle are seen occasionally at the midline and on the ipsilateral side, with dendrites toward the contralateral side. Motoneurons on the ipsilateral side do not display these features. In Pleurodeles, developmental brain processes are slowed down, and the sequence of development of the contralateral subnucleus, which can be clearly observed, supports the migration hypothesis. In Xenopus laevis and most other species of salamanders this process is accelerated.

Enlargement of regional lymph nodes in renal cell carcinoma is often not due to metastases.

Preoperative axial computerized tomography scans in 163 patients with renal cell carcinoma were reviewed to assess the predictive value for the diagnosis of regional lymph node metastases. Computerized tomography was falsely negative in 5 patients: 2 had metastatic lymph nodes in the renal hilus adjacent to the primary tumor measuring 2 and 2.5 cm., and 3 had micrometastases in nodes of less than 1 cm. In 43 patients enlarged lymph nodes with a diameter of 1 to 2.2 cm. (median 1.4 cm.) were diagnosed on the preoperative scan and this was confirmed at nephrectomy and pathologically. In 18 of these 43 patients (42%) histological study showed metastases of the renal cell carcinoma in the enlarged lymph nodes. In the other 25 patients (58%) the enlarged nodes showed only inflammatory changes and/or follicular hyperplasia. This finding was significantly more frequent in patients with tumor involvement of the renal vein and tumor necrosis (p = 0.0044). We conclude that the sensitivity of preoperative computerized tomography is good for the detection of enlarged lymph nodes in patients with renal cell cancer (95%). However, significant lymph node enlargement frequently may be caused by inflammatory changes, especially in the presence of tumor necrosis. This radiological finding should not be misinterpreted as metastatic disease, unless it has been proved cytologically by fine needle aspiration.

Oculomotor (N III) motoneurons can innervate the superior oblique muscle of Xenopus after larval trochlear (N IV) nerve surgery.

The position of motoneurons which reinnervate the superior oblique muscle (SOM), normally exclusively innervated by contralateral trochlear motoneurons, was studied in Xenopus using retrograde tracing techniques. The trochlear nerve was cut at its decussation in 49 larvae of different ages and, after subsequent regeneration, the total number of trochlear motoneurons was found to be reduced to about 50% of the controls. In contrast, the number of ipsilateral trochlear motoneurons was increased. Cutting the trochlear nerve at later stages may result in absence of this nerve. In some animals the SOM was innervated either by superior rectus or, more frequently, by inferior oblique motoneurons alone; the latter is known to act predominantly as an antagonist of the SOM.

Organization of the six motor nuclei innervating the ocular muscles in lamprey.

The topography of motoneurons supplying each of the six ocular muscles of the lamprey, Lampetra fluviatilis, was studied by selective application of HRP to the cut nerves of identified muscles. In addition, the distributions of motoneuron populations to both eyes were studied simultaneously with fluorescein and rhodamine coupled dextran-amines (FDA and RDA) applied to cut ocular muscle nerves of either side. The motoneuron pool of the caudal oblique muscle is represented bilaterally in the trochlear (N IV) motor nucleus. The dorsal rectus muscle is innervated from a contralateral group of oculomotor (N III) motoneurons and the remaining four muscles exclusively from the ipsilateral side (N III and N VI). The inferior and posterior rectus muscles are both innervated by the abducens nerve. In contrast to all jawed vertebrates, only three eye muscles (the dorsal rectus, rostral rectus, and rostral oblique) are innervated by the oculomotor nerve in lampreys (N III). Lampreys have a motor nucleus similar to the accessory abducens nucleus previously described only in tetrapods. They lack the muscle homologous to the nasal rectus muscle of elasmobranchs and the medial rectus muscle of osteognathostomes. The distribution of the dendrites of different groups of motoneurons was studied and is considered in relation to inputs from tectum and the different cranial nerves.