Release of daunorubicin from polymethylmethacrylate for the improvement of the local growth control of bone metastasis animal experiments.

Bone metastases are a sign of advanced tumor disease. Surgical therapy is only occasionally curative. Therefore, the therapeutic goals are a limited surgical excision, immediate mobilization, effective stabilization and the avoidance of local recurrence. We investigated the effect of the anthracycline daunorubicin (DNR) in conjunction with polymethylmethacrylate (PMMA) in vitro and in animal experiments for regional control of bone metastases. Previous experiments of local chemotherapy in bone metastases using methotrexate (MTX) were done by Langendorff and Hernigou. In our own experiments we improved the release of daunorubicin from polymethylmethacrylate in vitro and in vivo up to 90% by adding mannitol. In in vivo experiments we investigated the combination of DNR and PMMA in athymic nude mice and Wistar rats. Cells from human breast cancer, bronchial carcinoma, nephroma, and soft tissue sarcoma were subcutaneously implanted bilaterally under the dorsal skin of nude mice. After reaching a diameter of 0.5 cm, the tumors were marginally excised, leaving microscopic tumor residuum behind. The tumor cavities were either filled with PMMA or alternatively with DNR-PMMA. The goal was to avoid tumor recurrence in the DNR-PMMA filled resection cavities. The number of recurrences was significantly lower in the DNR-PMMA treated animals, except in the breast cancer group. Additionally we implanted a rat sarcoma intrafemorally into Wistar rats. After 17 days the tumor was marginally excised and the resection cavity was filled with either DNR-PMMA or PMMA alone. The therapeutic goal was to prevent local recurrence. Histological and pharmacological tests concerning toxicity and drug distribution within the body completed the study. We concluded that the addition of daunorubicin to PMMA supplements surgical resection. We were able to reduce the number of, or delay recurrences in our animal models. Systemic side effects could be minimized despite the achievement of high local drug concentrations.

[Synthetic replacement of the anterior cruciate ligament--effects on the remaining ligament structures]. / Synthetischer Ersatz des vorderen Kreuzbandes--Auswirkungen auf die verbleibenden Bandstrukturen.

In a three-dimensional anatomical knee joint model all major ligaments were replaced by six nylon fibers and length-pattern changes registered and computed during motion between 0-140 degree. Then anteromedial, posteromedial and intermedial fibers were replaced by an artificial ligament made from Aramid (one to three bundle prothesis) and length changes of the remaining ligaments investigated. The result revealed a dynamic feed-back with characteristic changes in the posterior and collateral ligaments in comparison to the reference. A synthetic replacement using a one bundle prothesis in the isometic tracking led to disapointing results. Best correlations were achieved mimicking the anatomic situation by use of a three bundle prothesis with nearly no changes in the length pattern of the remaining ligaments.

[Computer-assisted data analysis of injuries of the skeletal system in polytrauma patients]. / Computergestützte Datenanalyse von Verletzten des knöchernen Bewegungsapparates beim polytraumatisierten Patienten.

The data of 366 patients with multiple injuries were evaluated by application of data processing over a period of seven years. Age and sex distribution, location and combination of injuries, mortality, mechanism of accident, diagnostics as well as therapy were analysed. 91.3% of our patients had injuries of the skeleton. The male to female ratio was 2:1. In 55.4% the age of the patients ranged from 10 to 39 years. The mortality rate of all patients was 27.2%. In the third decade only 16.9% of the patients died. Whereas the mortality of the patients in the 1. decade as well as between the 7. and 9. decades of life was very high (33% and 50%). Most of the skeletal injuries were located in the shank (24% open fractures). The mortality rate increases with the number of injuries (Table III). Patients with concomitant injuries, such as head injuries and fractures of the extremities were the most common combination of multiple injuries. 20% of the patients in this group died. Patients with combined injuries of the head, chest, abdomen and skeleton had highest mortality (57%). X-ray examination of the skull, chest, extremities and mainly of the spine and pelvis should be subjects of routine diagnostics. In patients who were suspected of having a blunt abdominal trauma, the first diagnostic technique will be ultrasound. On account of the various number of concomitant injuries as well as the patients individuality, the estimation of prognosis by systems for the classification of the severity of injury is fraught with difficulties. The analysis of the evaluated data showed that previously small number of variables may predict the prognosis of the course of disease.

[The horizontal patellar dislocation]. / Die horizontale Patellaluxation.

The horizontal dislocation of the patella is a very rare event and little described in literature. On the occasion of a 35 years old motor car driver accident mechanism an therapeutic management are discussed.

[Functional treatment of joint fractures]. / Funktionelle Behandlung von Gelenkfrakturen.

The absence of functional load causes damage to different extents in various structures of the joint. Especially cartilage, joint capsule and ligaments are affected. Although operative functional treatment provides better prerequisites for avoiding such damage compared to conservative procedures, the results are not satisfactory in nearly 25% of the cases. Functional treatment of fractures of the joint by extension and continuous passive motion are suitable wherever operative reconstructions do not seem successful or have been proven to be superior as in fractures of the calcaneus.

[Bone cement containing cytostatic drugs: new aspects in the treatment of malignant bone tumors. I. Experimental studies]. / Cytostaticahaltiger Knochenzement: Neue Aspekte in der Behandlung maligner Knochentumoren. I. Experimentelle Untersuchungen.

Radical surgery in malignant bone tumors can either be limited by anatomical structures or seems inadequate in the palliative stabilization of bone metastases. Incomplete removal of the tumor and stabilization by compound osteosynthesis or endoprosthesis contains two problems: 1) the wide spread of malignant cells by manipulation in the tumor bearing area; 2) progressive destruction of bone due to remaining tumor. To overcome these problems we developed methotrexate bone cement (MTX-Palacos) with the aim to obtain high local concentrations of methotrexate in order to destroy remaining tumor cells and avoid systemic side effects. In vitro studies showed that methotrexate is released continuously from this cement without relevant changes of its biomechanical properties. Animal studies with transplanted osteosarcomas and mamma carcinomas in mice showed a considerable decrease of tumor growth when a plug of MTX-Palacos was inserted in the center of the tumor. Histological findings showed that in the surroundings of the plug the tumor was destroyed considerably contrary to normal bone cement which had no effect on the tumor at all. The results are discussed with regard to clinical application of MTX-Palacos.

[Results of surgical treatment of fractures of the metacarpus and fingers]. / Ergebnisse der operativen Behandlung von Frakturen der Mittelhand und Finger.

Ninety-one patients with 108 fractures of the metacarpal and/or finger bones were treated by surgery between January 1974 and June 1982. 70 patients (76.9%) with 81 surgically treated fractures could be checked up after 3 3/4 years on an average. 24.3% out of these patients suffered from associated soft tissue leasions, 25.7% suffered from multiple fractures. 41 out of the 81 surgical interventions were performed for fractures of the metacarpus and 40 for fractures of the finger bones. The results were classified according to an evaluation scheme established for this purpose and containing the following parameters: mobility, trophism and sensitivity, gripping functions, force, and X-ray findings. Subjective troubles were evaluated, too. The great value of osteosynthesis in the surgical treatment of the hand is confirmed by the overall results with 92% of very good or good results and 7% of satisfactory results in metacarpal fractures and 60% of very good or good results, 36% of satisfactory results and 3% of poor results in fractures of the finger bones, the more as patients treated by surgery represent a negative selection among all patients treated for fractures of the bones of the hand. The results were classified and evaluated according to fracture site, severity of associated injuries, and method of osteosynthesis applied.

[Late results in the treatment of subtalar dislocations]. / Spätergebnisse bei der Behandlung subtalarer Luxationen.

A follow-up study concerning arthrotic, ischemic and functional results was performed in 20 patients with subtalar luxations over an average of 13 years after the initial trauma. 13 patients showed good, 7 poor results according to Weber. 4 of these 7 patients were free of any complaints but showed reasonable arthrosis in both ankle joints as well as pathological scintigrams. Three cases operated upon showed poor functional results, two of them were primarily open, in one case the tendon of m. tibialis post. forced us to reduct openly. The best results could be obtained by immediate reduction and conservative treatment.

[The influence of cyclophosphamide upon the healing of fractures in the rabbit (author's transl)]. / Der Einfluss von Cyclophosphamid auf die Knochenbruchheilung am Kaninchenfemur.

The influence of cyclophosphamide (Ctx) upon the healing of fractures in the femur of the rabbit is reported. During treatment with Ctx the x-ray shows a reduced callus-formation; the fluorescence-microscopy reveals a decreased apposition of bone. Fracture-load, fracture-energy and mineral content of the intact bone are not influenced by Ctx. Four weeks after an operation fracture-load and fracture-energy are reduced almost by one half and the mineral content is decreased significantly.

[Results of surgical stabilisation of 307 open fractures (author's transl)]. / Ergebnisse der operativen Stabilisierung bei 307 offenen Frakturen.

Primary operative care with debridement and the soft tissue protective osteosynthesis is the method of choice in the management of open fractures. A follow-up study of 307 so treated fractures was performed over an average of 3 years after the initial trauma. The overall rate of osteomyelitis was 8.5% in below knee compound fractures and 4.9% in all other areas. During the past two years while using the external fixation device in 2nd and 3rd degree compound fractures in the lower leg the osteomyelitis rate was reduced to 5.5%. In the 2nd and 3rd degree compound crural fractures due to the delayed bone healing with the external fixation method alone we recommend the so called "combination osteosynthesis" in which a screw or a AO-2-hole-plate is employed additionally. Furthermore it seems essential to perform an autologous cancellous bone graft in these fractures to reduce the long healing time.

[The connecting osteosynthesis and its problems in unstable pertrochanteric fractures of the femur (author's transl)]. / Die Verbund-Osteosynthese und ihre Problematik bei instabilen pertrochanteren Femurfrakturen.

In unstable pertrochanteric fractures of the femur a high bending strain and much load lies on the medial part of the bone. The connecting osteosynthesis takes off this load and immediately guarantees a high stability. Clinical experiences with 44 cases of connecting osteosynthesis - among them 35 per-and subtrochanteric fractures of the femur-show, that in 11 cases complications due to the fractures occurred (breaking of the implant, pseudarthrosis etc.) These complications are probably due to a delayed healing caused by bone cement penetrating into the area of the fracture. It is recommended to use an autologous cancellous bone graft. Indications for the compound osteosynthesis are only unstable pertrochanteric fractures in old patients in poor general condition and a short life-expectancy, and fractures in patients with diffuse metastases.

[Results of stabilisation in pathologic fractures in the femoral shaft region by nailing (author's transl)]. / Ergebnisse der Stabilisierung pathologischer Frakturen im Femurschaftbereich mit dem Verriegelungsnagel.

The article reports on 11 patients with metastases in the femoral shaft. In 5 patients, a pathological fracture had occurred, whereas in 6 patients the femur, which was liable to fracture, was prophylactically stabilised by means of the femoral shaft nail. Eight of these patients were able to walk after the operation, whereas 4 patients died after an average period of 19 weeks following surgery of their primary diseases. The method employed in these cases was of a palliative nature, resulting in considerable relief from pain, improved ability to walk, and hence in an improvement of the quality of life of these patients.

[Fractures of the proximal and middle-third of the lower arm in childhood (author's transl)]. / Der Vorderarmschaftbruch des mittleren und proximalen Unterarmdrittels im Kindesalter.

53 children with fractures of the proximal or middle third of the lower arm and who were treated conservatively have been reviewed between 5 and 13 years after the accident. In 23% of the patients with fractures of the middle third of the arm, the results were unsatisfactory or poor. As the spontaneous ability correct in the intermediate third of the forearm is apparently less than in the proximal and distal thirds close to the epiphysis an axially corrected reduction should be aimed at in all cases. If this cannot be achieved by conservative means, then surgical intervention is necessary even in children.

[Healing of segmental defects in long bones. Animal experiments. Part II. Histological and micro-angiographical findings (author's transl)]. / Heilung von Segmentdefekten an Röhrenknochen. Tierexperimentelle Untersuchung. Teil II. Histologische und mikroangiographische Befunde.

In part I of this paper the radiological findings in segmental defects of long bones were discussed. The histological regeneration originates from the marrow cavity. An endostal framework of bone is formed; this is more pronounced on the proximal resection place than on the distal one. The new bone formation within the defect depends on the revascularization through medullar blood vessels. The increased osteogenesis on the proximal site of resection is due to the increased formation of vessels in this area. The vascularization and the filling of segmental defects in tubular bone occurs faster, if only one metal plate and on the opposite side an autologous bone graft (cortical bone) is used in order to stabilize the bone. This method is superior to the use of a double-plate osteosynthesis. The graft unites with the underlying bone within twelve weeks by forming a trabecular network of new bone. If the autologous bone graft has become stable, it is vascularized from the bone and from the sorrounding soft tissue. Afterwards an osteolysis and at the same time an osteogenesis take place. The dead bone graft is replaced by newly formed bone within about 40 weeks. The loss of stability which occurs does not endanger the osteosynthesis.

[On the problem of industrial accidents under drug influence (author's transl)]. / Zur Problematik der Arbeitsunfälle under Einfluss von Medikamenten.

Industrial accidents resulting from technical defects have decreased in the last eights because of improved safety precautions. In contrast, accidents resulting from "human error" are increasing steadily. Toxicological urine analysis for drugs--directed mainly at soporifics, sedatives, tranquilizers, and pain-relievers--on 84 patients involved in industrial accidents yielded the following results. 1. Drugs were identified in 44 patients (= 52%). 2. In 13.4 patients, more than one drug was identified (= 16%). 3. Only five of the 44 patients admitted on being questioned that they had taken drugs (= 10%). On the other hand, in a control group of 47 persons who and not suffered any accident, drugs were detected in 19 cases (= 40%). The results show that the physician will have to take into account that healthy and efficient persons, too, are very often likely to practise drug abuse. It must be considered probable that this helps to promote accidents. Medical prescription, especially of neuroleptics and psychotropics, as well as of sedatives, should be practiced more.