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Background: Wrist fusion is still a common treatment for patients with advanced stage arthritis. Since patients are often intimidated by the functional limitations, we intended to evaluate the influence of the lack of wrist motion in different positions on the dynamic grip function and the grip strength of the hand., Methods: We simulated wrist fusion in 20° extension and 20° flexion and evaluated the following grip types: fist closure, 2 different power grips, pinch grip and precision grip. A TUB sensor glove was used, which allowed us to dynamically record the range of motion (ROM) of the finger joints as well as grip strength. Nineteen healthy subjects participated and all types of grips were performed using a standardised protocol with and without simulated wrist fusion., Results: Lack of wrist motion in 20° extension had no relevant effect on the fingers' ROM, grip speed or strength. Simulated fusion in 20° flexion also had no influence on ROM or grip speed, rejecting our hypothesis that a tenodesis effect of the extensors in flexion would decrease ROM in the finger joints and grip speed. However, we were able to show a significant decrease of grip strength in flexion compared with extension or healthy wrists. The decrease averaged between 23 and 42% of healthy values, depending on the grip type. There was no change in strength distribution among the fingers., Conclusion: We didn't find any impact of lack of wrist motion on finger movement during forceful hand grip at normal speed. However, a significant loss of grip strength in flexed position of the wrist joint should be considered in patients with an indication for bilateral wrist fusion., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background/purpose: Joint replacement is a widely used procedure to treat painful osteoarthritis of the proximal interphalangeal joint. From 1996 to 1999, 16 patients received 19 hinged, piston-based DIGITOS prostheses in our department. In 2007, the 7-year clinical course of 14 patients (17 devices) was published in this journal. Now 12 of these patients (15 devices) have been followed with an average history of 17 years, and the preoperative data has been compared with the results after 7 and 17 years, respectively., Patients and Methods: The patients were 10 women and 2 men, whose average age at the time of the preoperative examination was 63 (48-69) years. Replacements were performed on the index (6), middle (6), and ring finger (3). There were 14 idiopathic osteoarthritic changes and 1 posttraumatic osteoarthritic change. Follow-up included a clinical (range of motion in the proximal interphalangeal joint, extension lag, pain) and radiological examination. In addition, the DASH score was obtained and the patients were asked whether or not they would undergo the same surgery again. The results after 7 and 17 years were reviewed for statistically significant differences., Results: While there were significant changes regarding extension lag and flexion in the first 7 years after replacement of the proximal interphalangeal joint, only minor changes were observed between 7 and 17 years after surgery. While the prosthesis was in its correct position in the first 2 years after implantation, all prostheses exhibited radiolucent lines after 4 years and periprosthetic osteophytes after 5 years. 17 years after surgery, the radiolucent lines had not increased at all and the osteophytes had increased insignificantly compared with the 7-year findings. None of the patients reported pain; all of them said that they would undergo the same surgical procedure again., Conclusion: While there were significant clinical and radiological changes in the first 7 years after replacement of the proximal interphalangeal joint by a linked DIGITOS prosthesis, only minor changes were observed between 7 and 17 years after surgery., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: In the treatment of small bone fractures, such as the scaphoid bone, conventional navigation is limited by its dependence on fixed reference arrays. We introduce a new technique based on reference markers in surgical instruments. If visible on a standard fluoroscopic image, static trajectories are overlaid in this image to guide implant insertions. Fixed markers are not required. The purpose of this study was to identify the possible advantages of the new guidance technique., Methods: For this study, 20 artificial hand specimens were randomized into two groups and blinded with polyurethane foam: 10 were treated conventionally and 10 were image guided. We used a clip containing radiopaque markers, which was detected by the system's workstation. A static trajectory was displayed consecutively in the fluoroscopic image to serve as an aiming device. Secondly, we included 3 patients with fractures of the scaphoid bone to test the integrability of this novel method in a clinical setting., Results: In the experimental setup, trajectory guidance reduced the duration of surgery and radiation exposure. Furthermore, it reduced the perforation rate. Accuracy was not improved by the new technique. For clinical cases, the system was integrated into the accommodated surgical workflow and rated as very helpful by users., Conclusion: The system helped reduce the misplacement rate and the emission of radiation. The main limitations were that trajectories were not displayed in real time and could only be shown in a single fluoroscopic image. However, the system is simple and can be easily integrated into the surgical workflow.

The purpose of this study was to assess whether there is a universal pattern of movement of the finger joints while performing a cylinder grip. A sensor glove was used to record the finger joint motion of 48 participants. Our observations showed that when examining the fingers, flexion motion began either at the metacarpophalangeal (MP) or proximal interphalangeal (PIP) joints, with the distal interphalangeal (DIP) joints always last to move (p = 0.0052). The sequence of the joints at the end of the gripping motion was different than at the beginning. Here, the only statistically significant observation was that the DIP joints fully flexed only once the MP joints had flexed fully. Apart from that, it was completely variable which joint reached its final position first or last. The analysis also revealed that synchronization of four identical joints (i.e. the four PIP joints) was significantly higher than synchronization of the 12 finger joints. Although synchronization was already high at the beginning of the flexion motion, it increased significantly by the time the joints completed their movement.

In the case of a patient with a large pyogenic granuloma of the thumb about three months after the bite of a sheep, we covered the defect after resection with a split thickness skin graft. Although at first amputation was discussed, after a few months a very good functional and aesthetic result was achieved., (Georg Thieme Verlag KG Stuttgart · New York.)

The present study analyses force distribution patterns during primary grips. 10 subjects were examined using the TUB-sensor glove, which was equipped with 10 pressure sensors. 5 proximal sensors at the MCP joints and 5 distal sensors at the DIP joints were attached palmarly. 9 different gripping motions were examined: the cylinder grip using 4 different objects, the pinch grip and 4 different kinds of precision grips. The force distribution patterns can be clearly divided into 2 groups. On the one hand there are the "power grips", in which the force is distributed over the proximal and distal sensors. On the other hand there are the "precision grips", which only show a force distribution at the distal sensors. Therefore Napier's concept of the existence of primarily 2 gripping patterns, which is based on visual analysis, can be verified objectively. For the "power grips" the force distribution is shifted further distally with increasing size of the objects. In conclusion, their distribution pattern shifts towards the pattern of the "precision grips". At the small finger the distal sensor is already dominant during the "power grips" of smaller objects. The thumb plays a subordinate role during the "power grip" of smaller objects, since these grips are similar to the "closing fist motion" and the objects can be held between the fingers and the palm of the hand. However, with increasing object sizes the thumb gains more importance, since its opposing movement is now required to accomplish the grip., (© Georg Thieme Verlag KG Stuttgart · New York.)

The purpose of this study was to analyse motion patterns of the finger joints dynamically while making a fist. 10 subjects were examined using the TUB-sensor glove, which was equipped with 14 joint angle sensors. The median time it takes the finger joints to complete flexion until reaching the state of a closed fist ranges between 0.5 to 1.0 s. A specific pattern can be seen for every finger. The PIP and DIP joints appear to be linked, with the DIP trailing the PIP joint. At the thumb the IP is trailing the MCP joint. The MCP joint shows more variation at the beginning of flexion: while in some cases it initiates movement in a finger, in other cases its flexion falls behind the PIP joint movements. The completion of flexion is achieved by the MCP joints, with the PIP and DIP joints reaching their end of motion first. The range of motion (ROM) at the MCP joints shows a finger-dependent median of 79-97°. At the PIP joints the median lies between 87° and 90°, at the DIP joints between 52° and 68°. At the thumb it is 21° for the MCP and 24° for the IP joint. The linkage between PIP and DIP joints can also be seen when analysing the ROM. The coupling ratio amounts to 0.77 at the index finger, 0.75 at the middle and ring finger and 0.57 at the small finger., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: To determine whether the grip of a healthy subject's hand shows certain universal characteristics. To accomplish this, we examined the complex interactions of the fingers during gripping of different-size cylindrical objects., Methods: A total of 48 subjects (11 women, 37 men) performed 5 cylinder grips with different object sizes. The 14 joint angular profiles of the 5 digits were measured dynamically with a Technische Universität Berlin sensor glove., Results: Frequently, initial movement was detected before the actual grip. This movement consisted of passive flexion of the fingers the moment the hand rose from the table, followed by active extension of the fingers before gripping the object. Along with the type of joint, the size of the object gripped influenced the frequency of these initial movements (p<.001). During actual grip, the proximal interphalangeal joints' flexion was significantly greater than the flexion of the metacarpophalangeal and distal interphalangeal joints (p<.001). The mean flexion of the proximal interphalangeal joints was 43 degrees , that of the metacarpophalangeal joints was 28 degrees , and that of the distal interphalangeal joints was 26 degrees. Apart from these findings, the larger the flexion angle was, the more time tended to be needed to fulfil the motion., Conclusions: The results show that there is a universal motion pattern with the cylinder grip in healthy individuals concerning the range of movement of the finger joints. However, to fully understand the cylinder grip in healthy individuals, our next step will be to analyze the dynamics of the cylinder grip as well. For that purpose, we examine the dynamic interactions between the fingers--that is, their chronological sequence during the cylinder grip., (Copyright 2010 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Most important methods for the surgical treatment of painful arthritis of the proximal interphalangeal joint are the joint fusion or the implantation of a prosthesis. There are a lot of different models for joint replacement. Sixteen patients received 19 middle joint replacements performed with the DIGITOS-prosthesis between 1996 and 1999. Over a period of seven years, 14 patients with 17 prostheses have been observed prospectively. In the 7-year follow-up, a minimal radiolucent line at the bone-cement junction and huge periarticular osteophytes could be found in every case. No cortical penetration, luxation, or implant fractures were recorded. The preoperative median range of motion was 50 degrees. Postoperatively, there was an improvement to 60 degrees. The range of motion decreased to 50 degrees after one year and to as little as 30 degrees after seven years. Preoperatively, eleven patients had pain with activity and three had pain without activity. During the whole follow-up period there were only two patients who had pain at work. All patients were satisfied with the results of the operation throughout the control period and would choose the same treatment again.

Background: The estimation of the time off work depending on the injury pattern and severity is of major interest in the treatment of hand injuries. The predictive value of the HISS score (Hand Injury Severity Scoring System) was evaluated., Material and Methods: According to this score, 184 work-related injuries (1999 to 2002) were analyzed prospectively, excluding injuries of both hands. The median age was 37.9 years (18 to 65 years), 11 % of the patients were female., Results: A significant correlation was established between the HISS score and the time off work (p < 0.0001, r = 0.51). The score also correlated with the degree of work incapacity (p < 0.0001)., Conclusion: Our data confirm the predictive value of the HISS score for the early estimation of the time off work resulting from hand injuries. However, the estimation is limited to injuries distal to the wrist.

In contrast to the standard therapy of flexor tendon injuries in adults, the postoperative treatment program for children remains a controversial topic. Some prefer immobilization therapy in a variety of forms and for different periods of time. Others prefer early mobilization programs. We present results for twenty-eight children with thirty-seven flexor tendon injuries. The average age was 5.8 years. After primary tendon suture in children six years and younger (group A), our postoperative program consisted of immobilization for three weeks. The older children (group B) were treated with an early passive mobilization program. Follow-up examinations were carried out on twenty six of the children at three months and at 3.7 years. Three months after surgery, the children in group A showed only average results while those in group B presented good finger motion. After 3.7 years both groups showed good results.

The de novo synthesis of a full set of hydroxymethyl C-glycosides from only two precursors is described. The seven-carbon target molecules contain five stereocentres and bridge the stereochemical gap between natural D-configured and non-natural L-configured series of hexoses. Key steps include hydroxylation, differential protection, stereoselective reduction and desymmetrization of 8-oxabicyclo[3.2.1]oct-6-enes. C-Terminus differentiation and C-terminus excision of the seven-carbon polyol backbone lead to hexoses, including those of the L-series. A stereochemical and genetic classification of C-glycosides is presented.

In dynamic and static scapholunate instability after trauma, the repair of the scapholunate ligament is important to avoid scapholunate advanced collapse of the wrist. Direct suture even of fresh-torn ligaments can be technically demanding and occasionally unreliable, thus reconstruction may require additional tissue beside the ligament. Eighteen patients suffering from dynamic (n = 10) and static (n = 8) scapholunate instability were treated by a dorsal ligament reconstruction six months after trauma. A clinical wrist score according to Cooney showed an average of 86 points (maximum 100) within a follow-up of nineteen months after surgery. X-ray films documented no significant loss of scapholunate reduction. Using local tissue only, this method is always possible, very reliable and easy to perform.

Objective of this study is to compare clinical and radiological results of two different methods of treatment for trapeziometacarpal osteoarthrosis of the thumb. Eighteen patients received operative treatment. An operation according to Epping was performed in eleven cases (collective I), while nine cases were treated with a trapeziectomy only (collective II). The mean follow-up of the first collective was 40 months and 15 months for the second one. The results of the two patient groups were subjected to statistical comparison in a retrospective study. This revealed no significant differences with regard to active range of motion, power, and subjective symptoms, classified according to the Buck-Gramcko score. With a mean of 49 points for the first and 50 points for the second collective, both achieved very good results. However, the mean operating time was significantly shorter in the patients treated with a trapeziectomy only, while the mean distance between the base of the first metacarpal bone and the scaphoid bone was significantly greater in this group. This is surely due to the shorter follow-up of the patients who underwent trapeziectomy only, since further proximalisation has to be expected. We were able to demonstrate that both methods yield equally good results, and hence the simpler technique of trapeziectomy alone should be given preference, at least in the standard situation of a patient, whose intermetacarpal ligaments offer sufficient stability after trapeziectomy.

The high importance of intracortical porosity for mechanical strength of cortical bone has been established. The contribution of other parameters of microstructure such as osteon dimensions for strength is in discussion. The aim of this study was to evaluate the predictive value of microcomputed tomography (mCT) for porosity and other microstructural parameters of cortical bone in cortical bone biopsies. Femoral cortical bone specimens from the middiaphysis of 24 patients were harvested during the procedure of total hip replacement at the location where normally one hole (Ø 4.5 mm) for the relief of the intramedullary pressure is placed. In vitro intracortical porosity and bone mineral density (BMD) measurements by mCT were compared with structural parameters assessed in histological sections of the same specimens. A strong correlation was found between intracortical porosity measured by mCT and histological porosity (r = 0.95, P <0.0001). Porosity measured by mCT was also a strong predictor for other parameters describing dimensions of porous structures. BMD?1 was associated with osteonal area (r = -0.76, P <0.0001). We consider the measurement of porosity by mCT as a very potent procedure for assessing intracortical porosity and parameters related to porous structures of cortical bone nondestructively in vitro.

Joint angles are measured using goniometers according to the neutral-zero method. These measurements are dependent on the examiner and are thus subject to great variation. With a newly developed sensor glove, the grip patterns of the hand can be captured with a computer-assisted technique. In a comparative study involving five subjects, the joint angles during power grip around a cylindrical body and while clenching a fist were determined by nine examiners at three different times, using the conventional technique according to the neutral-zero method. In the same experimental design, the joint angles were measured with the sensor glove. As a criterion for the reproducibility of the measurements, the intraclass correlation coefficient (ICC) was calculated by means of an analysis of variance. The ICC is a value which approximates 1 if the reliability of the measurements is high. At 0.94, the ICC of the data determined with the sensor glove was markedly higher than the mean ICC for all examiners of 0.50 using the conventional method. Besides the measurement of the finger joint angles, the sensor glove allows the dynamic recording of joint movements of all finger joints during different grip patterns of the hand.

Grip strength measurements with the aid of dynamometers are dependent on the cooperation and motivation of the individual examined. Recognising a simulated loss of grip is a hitherto unresolved problem. With a sensor glove developed at the Berlin University of Technology, the force distribution pattern of any form of grip can be captured via ten pressure sensors and evaluated by computer. In five subjects, the force distribution patterns at submaximum and maximum force of five different grips were determined in three successive measurements each. The data were recorded in force-time diagrams. For each act of grasping, the measurements produced a curve with near-constant measuring signals within a defined period (plateau). The difference in the plateau heights of successive grips and the structures of the individual plateaux (oscillation, standard deviation) were used as distinguishing criteria. The dynamics of the measuring signals showed statistically significant differences between grips with submaximum and maximum force (p < 0.0001).

The treatment of osteoarthrosis of the proximal interphalangeal joint by prosthesis bears several specific problems. With the DIGITOS-prosthesis a new implant is now available. It is a cemented modular hinged prosthesis. We report our experiences with this implant from a prospective clinical trial. Seven patients with osteoarthrosis of the proximal interphalangeal joint had ten prosthetic middle joint replacements performed with DIGITOS-prostheses. Over an observation period of two years, the functional results were found to be good. The mean preoperative range of motion in the affected joints was 51.5 degrees. Three months after surgery, this had improved to 60.5 degrees, but then decreased to 53.0 degrees after one year and to 49.5 degrees, i.e. the original range of motion, by the end of the second postoperative year. No implant became loose. Nearly all patients were free from pain. The only serious complication was an iatrogenic lesion of the middle slip of the extensor aponeurosis resulting in a buttonhole deformity. In spite of these encouraging two-year results, the further follow-up has to be observed carefully.

It has previously been reported by the authors that the induction of a series of cytokines by 41.8 degrees C Whole Body Hyperthermia (WBH), i.e., interleukin (IL)-1 beta, IL-6, IL-8, IL-10, tumour necrosis factor alpha, and granulocyte colony stimulating factor (G-CSF). As cytokine levels are known to fluctuate as a function of time, i.e. circadian rhythm, the influence of circadian time structure on specific haemotopoetic growth factors is studied, i.e. granulocyte macrophage colony stimulating factor (GM-CSF), G-CSF and IL-3. Samples derived from four cancer patients undergoing extracorporeal WBH resulted in the following observations: G-CSF is induced by WBH, but unaffected by circadian rhythm, IL-3 fluctuates with circadian rhythm, but is unaffected by WBH. Specifically, a biphasic temporal pattern of IL-3 (i.e. with a peak at 2:00 and 5:00 a.m. and a nadir concentration at 5:00 p.m.) was found by analysis of variance. GM-CSF was below the lower detection limit pre and post WBH. The data show the importance of measuring cytokines as a function of time to circumvent conflicting results in the inter-relationship of 'true' cytokine induction and circadian rhythm. The implications of the differential induction of G-CSF, GM-CSF, and IL-3 for myeloprotection after WBH are discussed.

Whole Body Hyperthermia (WBH) has been shown to have physiological effects on myeloid and megakaryocytic haematopoietic tissue via both cytokine induction, as well as hormonal changes. In order to extend this knowledge base to the erythroid cells, endogenous erythropoietin (EPO) levels were studied in 17 cancer patients receiving 41.8 degrees C WBH and/or chemotherapy, as well as in 53 anaemic and non-anaemic control patients. Pre-treatment EPO levels showed a 'blunted' EPO response in cancer patients compared to the control patients. Post-treatment data demonstrated a significant chemotherapy induced increase in EPO levels with a peak at 36 to 48 hours (independent of changes in haemoglobin) and 10 to 13 days post chemotherapy (simultaneously with a drop in haemoglobin levels). The early change in EPO levels was not influenced by the addition of 41.8 degrees C (x 60 min) WBH to the same chemotherapy regimen, i.e., ifosfamide, carboplatin, and etoposide. Taken collectively, our data show that endogenous EPO levels in cancer patients can be effected by chemotherapy (independent of changes in haemoglobin). This EPO response to chemotherapy is not impacted on by 41.8 degrees C WBH. A relevant secondary conclusion can also be derived from this investigation, i.e., caution should be exercised as to the use of EPO levels during chemotherapy as predictors of exogenous EPO efficacy.

Preclinical studies are consistent with the concept that 41.8 degrees C whole body hyperthermia (WBH) can enhance the therapeutic index of specific chemotherapeutic agents. These laboratory investigations resulted in 2 phase I clinical studies, which also support this hypothesis. These trials were extended to 2 sequential phase II investigations of WBH plus ifosfamide, carboplatin and etoposide (ICE) for refractory sarcoma patients. The first study (involving 12 patients) using extra-corporeal WBH was prematurely closed to adopt a less toxic WBH technology, i.e., the radiant heat Aquatherm. To date, 12 patients have been accrued to the Aquatherm trial. Projections regarding reduced morbidity were correct. The response rate for ICE/WBH is currently 63%. The review to follow will summarize the results of these trials, as well as the laboratory and clinical data which serve to explicate the dramatic clinical results observed to date.

Preclinical data is consistent with the concept that the timing of chemotherapy during radiant heat-whole body hyperthermia (WBH) should affect therapeutic index. In order to test this hypothesis, a controlled clinical investigation was initiated. Patients received carboplatin (CBDCA) on an early or late schedule with respect to achieving target temperature (i.e. 41.8 degrees C) in alternating treatment cycles. The first cycle was randomized between patients regarding the early or late schedule for two planned sets per patient (i.e. four cycles). Ifosfamide, etoposide and granulocyte colony stimulating factor were delivered during all cycles with a standardized schedule. A total of 53 cycles involving 17 patients were analyzed. Detailed toxicity evaluation (i.e. delay in therapy secondary to thrombocytopenia, need for platelet transfusions, and days of hospitalization) taken collectively demonstrated a statistically and clinically significant advantage to delivering CBDCA 10 min after target temperature, during the plateau phase of WBH.

In the Department of Traumatology at the University of Ulm, 26 elderly patients with displaced acetabular fractures were treated with primary implantation of a hip joint endoprosthesis between 1986 and 1996. The principles of operative therapy are stabilization of the acetabular ring, grafting of acetabular defects with autogenous corticocancellous bone and cranial buttressing with a reinforcing ring. This concept permits immediate mobilization of elderly patients and full weight-bearing and thus results in favorable early postoperative results. Secondary complications typically caused by immobilization can therefore be avoided.

The goal of the present article was to determine whether a nuclear parameter, centromere structure of interphase cells, could serve as an indicator to assess cellular damage caused by anti-tumor drugs. These were cis-platin and mafosfamide, which are widely used for the management of solid tumors. To visualize the centromeres, we probed treated and untreated cells of a human breast cancer cell line, MX-1, with a human anti-centromere serum. The serum was obtained from a scleroderma patient and detects antigens associated with prekinetochores of the decondensed chromosomes. The DNA was simultaneously displayed by a specific fluorescent dye. The cells were grown on coverslips, incubated for 1 h in a drug-containing medium, transferred into a drug-free medium and observed 24 h later. Since the efficiency of many anti-tumor drugs increases with the temperature, two different temperatures, 37 and 42 degrees C, were used. The analysis revealed that the treatment did not visibly alter the labeling pattern. We conclude that chromosome structure remains largely intact and is not suitable for the cytological evaluation of the efficiency of anti-tumor drugs. This is in contrast with, for example, the microtubular cytoskeleton and mitochondria, which were extensively damaged under the conditions applied here (compare Wolf et al. 1995). Independent of the drug and the temperature selected, the nuclear lumen of mononucleated and multinucleated cells contained small fluorescent spots. Double dots corresponding to the sister centromeres in the G2 phase of the cell cycle were rare. In addition to the voluminous nuclei, some cells possessed micronuclei in the lateral cytoplasm and these were regularly labeled by the autoantibodies. A small subset of the mononucleated MX-1 cells had unusually large nuclei. It is reasonable to assume that they are polyploid. The fluorescent spots marking the prekinetochores were very large in these cells. This may indicate that the chromosomes remain associated after replication.

We have used a CREST anti-centromere serum and a DNA-specific fluorescent dye to study the composition of extended cytoplasmic bridges between interphase cells of a human carcinoma cell line, MX-1, grown on coverslips. Under natural conditions, approximately 8% of the cells possessed cytoplasmic bridges up to 60 microns long. Elongated extensions from the cell surface were also observed and were interpreted as severed cytoplasmic bridges. The bridges were extremely slender throughout most of their lengths and could not be properly resolved by phase-contrast microscopy. Staining with a DNA-specific fluorescent dye revealed, however, the presence of a thin DNA thread. This finding strongly suggests that the bridges arise during mitosis through faults in chromosome segregation. The bridges persist and most probably elongate, when the cells separate from one another after completion of mitosis. Some bridges showed also highly fluorescent DNA masses, which were detected by a CREST anti-centromere serum. Thus, a subset of the cytoplasmic bridges contained centromeres. The DNA-containing bridges between carcinoma cells in culture signal continuous rearrangements of the karyotype at a relatively high rate. The presence of extended cytoplasmic bridges between the cells could be a morphological marker for highly mobile tumor cell types and has, therefore, diagnostic value.

The present investigation is concerned with the morphological features of the human breast carcinoma MX-1, transplanted subcutaneously into nude mice. Three weeks after transplantation the tumor tissue is clearly distinct from the dermis. Solid tumor cell groups are separated incompletely by thin connective tissue septa, giving rise to a lobular appearance. The tumor cells are characterized by very irregularly formed nuclei with three or more nucleoli. The cytoplasm of these cells displays some lysosomes, the cisternae of the rough endoplasmic reticulum, mitochondria and a variable number of ribosomes. The Golgi fields are frequently observed, particularly near the nucleus. The cells are connected to each other by desmosomes, which also persist during mitotic activity. Ductular formations can occasionally be seen. The ultrastructure of the blood vessels discloses the morphological features necessary for the regulation of blood flow. Capillaries present a sinusoidal aspect with distended and narrow lumina. Interruptions of the endothelial wall, however, were not observed. This morphological appearance was found in all the MX-1 tumors investigated, reflecting the stable growth of this tumor cell line in nude mice.

The purpose of this study was to evaluate the pharmacokinetics, biological interactions, and toxicities of ifosfamide and carboplatin combined with 41.8 degrees C whole-body hyperthermia (WBH) for 1 h in a pilot clinical study. Nineteen patients with refractory sarcoma or malignant teratoma were treated. To obtain baseline pharmacokinetic data for ifosfamide, the first chemotherapy course was given without WBH in six patients. This enabled comparison of systemic toxicity and pharmacokinetics of the drug combination with and without WBH (+/- WBH). All other patients received three thermochemotherapy treatments every 3 weeks. Ifosfamide was escalated from 5 to 10 g/m2 with a fixed carboplatin dose of 480 mg/m2. WBH was induced by extracorporally heated blood (in a hemodialysis apparatus) with general anesthesia. The drugs were given at target temperature. A total of 49 thermochemotherapy treatments was administered. The use of the hemodialysis device resulted in an approximate one-third reduction of blood concentrations of 4-hydroxyifosfamide, one activated intermediate metabolite of ifosfamide and carboplatin, but in an increase of chloroacetaldehyde, the other main ifosfamide metabolite. The WBC counts and the platelet nadirs (up to WBH grade 4) were not significantly different +/- WBH. Of 19 evaluable patients, 7 partial remissions, 8 disease stabilizations (average duration, 3 months), and 4 patients with progressive disease were observed. There was no WBH-related mortality. Toxicities observed included mild (anasarca, diarrhea, pressure sores, and perioral herpes simplex) and severe (reversible neuropathy, cardiopulmonary distress, and severe renal dysfunction). No hepatic or central nervous system toxicity occurred. Nephropathy was the dose-limiting toxicity. In conclusion, ifosfamide and carboplatin can be administered with extracorporally induced WBH with acceptable toxicity. Results obtained are consistent with continued evaluation of this combined modality approach.

The influence of tumor temperature (28, 32, 37, 39, 41, or 43 degrees C for 1 h) on the therapeutic efficacy of i.v. single bolus injections of ifosfamide (IFO) (32, 65, 125, or 250 mg/kg body weight) in human tumor xenografts (MX1 breast carcinoma) grown in nude mice (n = 240) was studied. Tumor temperature was controlled by water bath immersion. Sixty days after treatment the percentage of tumor-free survival was determined. For example, at 37 degrees C IFO in a dose of 65 mg/kg body weight led to 10% tumor-free survival in the treated animals. At 43 degrees C the same dose resulted in 60% tumor-free survival. A clear drug dose- and temperature-dependent increase of the therapeutic efficacy of an active oxazaphosphorine compound was also demonstrated in vitro. The concentrations of IFO and of 4-hydroxyifosfamide in blood and tumors at different body temperatures (controlled by water bath immersion) were determined over 120 min and WBC counts were obtained. The half-lives and the areas under the curve for IFO in blood were not significantly different at 37 degrees C and 41 degrees C. Since the half-life of IFO depends mainly on hepatic metabolism, the similarity of half-lives and of areas under the curve for IFO at 37 degrees C and 41 degrees C indicates a constant activation rate. However, significantly lower plasma concentrations of the activated drug at a liver (body) temperature of 41 degrees C, compared with 37 degrees C, were found, indicating a higher elimination rate. The concentration of the activated drug in the tumors within the initial 60 min at 41 degrees C, however, exceeded by > 2-fold that at 37 degrees C. The bone marrow toxicity of the same drug dose did not significantly increase with body temperature.