Increased bone formation and osteosclerosis in mice overexpressing the transcription factor Fra-1.

Bone formation by osteoblasts is essential for skeletal growth and remodeling. Fra-1 is a c-Fos-related protein belonging to the AP-1 family of transcription factors. Here we show that transgenic mice overexpressing Fra-1 in various organs develop a progressive increase in bone mass leading to osteosclerosis of the entire skeleton, which is due to a cell-autonomous increase in the number of mature osteoblasts. Moreover, osteoblast differentiation, but not proliferation, was enhanced and osteoclastogenesis was also elevated in vitro. These data indicate that, unlike c-Fos, which causes osteosarcomas, Fra-1 specifically enhances bone formation, which may be exploited to stimulate bone formation in pathological conditions.

Histological demonstration of healing in experimental aneurysms.

INTRODUCTION: Recanalisation of aneurysms after interventional therapy is still an unsolved problem. The aim of this study is to demonstrate the angiographic and histological evidence of healing after endovascular embolisation of experimental aneurysms. METHODS: We evaluated the healing reaction in experimental aneurysms treated with HydroCoils and platinum coils. After microsurgical construction of aneurysms in 24 rabbits, embolisation was performed. Four animals were sacrificed immediately after embolisation and 5 after 1 month, 3 months and 6 months, respectively, the remaining served as control group. Serial plastic-embedded ground sections of the parent arteries-aneurysm complexes were evaluated by light microscopy. RESULTS: Thrombus organisation in the aneurysms resulted in fibrovascular tissue formation between bare platinum and HydroCoils from the walls of the aneurysms towards the centre of the sac over time. In the clefts between HydroCoils only thin strands of granulation tissue were observed. From one month on, there was a neointimal layer covering the coil mass at the aneurysm orifice. CONCLUSION: Progressive occlusion by the expanding hydrogel polymers on the coils seemed to result in a durable healing reaction in the aneurismal sac in a short-term follow-up period.

Cartilage and bone neoformation in rabbit carotid bifurcation aneurysms after endovascular coil embolization.

Occurrence and histomorphology of cartilage and bone neoformations was retrospectively evaluated in rabbit experimental aneurysms after endovascular coil embolization. During product development, 115 carotid bifurcation aneurysms were treated with hydrogel-containing devices (HydroCoil or target, n=77; HydroSoft or target, n=28; prototype Hydrogel-only, n=10; MicroVentionTerumo, Aliso Viejo, CA). Additional 29 aneurysms were treated with standard (n=22) or with degradable polymer-covered (n=7) platinum coils. After 4 to 52 weeks, the retrieved aneurysms were methylmethacrylate embedded, and ground sections were surface-stained with Rapid Bone Stain and Giemsa solution. Cartilage and/or bone tissue was assessed by light microscopy; respective tissue areas in the aneurysms were determined by computerized histomorphometry. Cartilage neoformation was observed from 26 to 52 weeks. Single chondrocytes to hyaline or fibrous cartilage areas, occupying up to 29% of the aneurysm cavity, were found in 6 aneurysms, treated with HydroCoil (n=4), Hydrogel-only (n=1), and resorbable polymer (n=1) devices. Chondral ossification associated cartilage neoformation in 2 of these 4 HydroCoil-treated aneurysms. Membranous woven and lamellar bone ossicles were observed from 13 to 52 weeks in 7 aneurysms, treated with HydroCoil (n=3) and platinum coil (n=4) devices. Altogether, cartilage and/or bone neoformation was observed in 13 (9%) of 144 rabbit bifurcation aneurysms treated with various embolic devices. Incidence was low until 26 weeks, but increased at 52 weeks in both, HydroCoil and standard platinum coil treated aneurysms. As the neoformations were predominantly located in proximity to the aneurysm neck, they could be related to the long-term mechanobiology of cell differentiation during fibrovascular healing of blood flow-exposed embolized aneurysms.

Retrieval analyses of highly cross-linked polyethylene acetabular liners four and five years after implantation.

Two Durasul highly crosslinked polyethylene liners were exchanged during revision surgery four and five years after implantation, respectively. The retrieved liners were evaluated macroscopically and surface analysis was performed using optical and electron microscopy. A sample of each liner was used to determine the oxidation of the material by Fourier transform infrared spectroscopy. Samples of the capsule were examined histologically. The annual wear rate was found to be 0.010 and 0.015 mm/year, respectively. Surface analysis showed very little loss of material caused by wear. Histological evaluation revealed a continuous neosynovial lining with single multinucleated foreign-body giant cells. Our findings showed no unexpected patterns of wear on the articulating surfaces up to five years after implantation and no obvious failure of material.

Analysis of postoperative radiation therapy in stage I through III epithelial ovarian carcinoma.

A retrospective long-term analysis of the results of primary postoperative radiotherapy in 106 women with invasive epithelial ovarian carcinoma is presented. Forty-two women received open-field total abdominopelvic irradiation, and 64 received treatment by various subtotal abdominopelvic techniques. The mean follow-up of living patients in the two groups is 86 and 116 months, respectively. Women who had Federation International Gynecology and Oncology (FIGO) stages I through III-A with no postoperative residual disease, or less than 0.5-cm abdominal and/or less than 2-cm pelvic residual disease formed a favorable group in whom total abdominopelvic irradiation resulted in a 71% 10-year actuarial relapse-free survival rate compared with 40% for those treated by subtotal abdominopelvic techniques (P less than or equal to .0205). The survival improvement due to the total abdominopelvic technique in favorable patients became even more significant (P less than or equal to 0.003) after adjusting for differences in stage, grade, and postoperative residual disease volume (no, or favorable, gross). Increasing grade appeared to be associated with decreasing survival even among favorable patients treated with the optimal technique, although the differences did not approach statistical significance after adjusting for residual disease volume and stage. Surgical bowel complications were equivalent, 7.1% for total abdominopelvic v 8.1% for subtotal abdominopelvic techniques. The addition of intraperitoneal radioactive chromic phosphate increased the surgical bowel complication rate 33% over external pelvic irradiation alone without improving survival. Patients with unfavorable gross residual disease and/or FIGO stages III-B and IV were incurable by any radiation technique. Those with no, or favorable, gross residual tumor constitute a group in whom we believe open-field total abdominopelvic irradiation represents a potentially curative therapy modality.

Mineral crystals in calcified tissues: a comparative study by SAXS.

The shape, the typical orientation, and the average size of mineral crystals in different types of mineralized tissues were investigated by means of small-angle x-ray scattering (SAXS). To rule out eventual artifacts due to sample preparation, four different standard preparation techniques were used and a comparison showed that the SAXS results were identical for all four methods. In mineralized turkey leg tendon, a frequently used model system for bone, the crystals were found to be typically plate-like with a thickness of the order of 2 nm. This stands in contrast to the case of bone (calvaria, femur, and iliac crest) from mouse, rat, and dog, where mainly needle-like crystals were found. The thickness of these crystals ranged from 3 to 4 nm but was remarkably constant for different bones of a given animal. The preferred orientation of the needle-like crystals was along the main axis of the femur and within the surface of the calvaria (for mouse, rat, and dog). The mineral plates in turkey leg tendon were located inside the hole zone and oriented along the fibril axis. Finally, no periodic arrangement of the crystals inside the hole zone of the collagen could be found.

Auditory ossicle abnormalities and hearing loss in the toothless (osteopetrotic) mutation in the rat and their improvement after treatment with colony-stimulating factor-1.

Osteopetrosis describes a group of skeletal metabolic diseases of heterogeneous etiology and varied severity that produces a generalized accumulation of skeletal mass, the result of reduced bone resorption. Inherited in a variety of species including humans, the most severe forms are lethal. Among common features are progressive blindness and deafness of controversial etiologies for which there are no universally effective treatments. We have studied the auditory responsiveness and auditory ossicle quantitative histomorphology and temporal bone vasculature in the toothless (tl) rat, a lethal osteopetrotic mutation with few osteoclasts, very low bone turnover, and limited angiogenesis in the axial skeleton. Compared with normal littermates, 3-week-old mutants showed significantly reduced auditory responsiveness, a hearing loss due to abnormalities in both form and tissue composition of the stapes, and little capillary sprouting in the vascular bed of the temporal bone. Treatment of mutants with colony-stimulating factor 1 (CSF-1), known to greatly reduce sclerosis in the axial skeleton, significantly improved hearing, stapedial form and tissue composition, and angiogenesis in the temporal bone. In normal rats, the stapes consisted of 89.3% bone, 9.1% mineralized cartilage, and 0.8% porosity. In osteopetrotic rats, the stapes consisted of 48.3% bone, 35.9% mineralized cartilage, and 15.9% porosity, while after CSF-1 treatment, the bone content increased to 55.2%, cartilage was decreased to 21.7%, and porosity increased to 23.0%, respectively. This is the first demonstration of an auditory abnormality in an osteopetrotic animal mutation and shows that the hearing loss in tl rats can be significantly improved following treatment with CSF-1.

Evidence for reperfusion injury in cortical bone as a function of crush injury ischemia duration: a rabbit bone chamber study.

A model for critical limb ischemia was produced by occluding femoral vessels in 24 rabbits with a pneumatic cuff for 0, 2, 4, or 6 hours. Immediate sequelae and subsequent creeping substitution of cortical bone were observed in vivo using an implanted tibial window, the optical bone chamber implant (with intravital microscopy), and then by light and fluorescence microscopy of fluorochrome-labeled and surface-stained ground sections of retrieved implants. Six rabbits were used as controls (0 h) for each ischemia treatment, and the animals were monitored for 5 weeks postocclusion. A subpopulation of 13 implants was retrieved after euthanization and then histologically assessed for bone necrosis and remodeling. The hypothesis tested was that reperfusion injury during the 24 h after occluder release (reperfusion phase), and vessel perfusion/caliber, angiogenesis, and net bone resorption during the 5 subsequent weeks (creeping substitution phase), would exhibit ischemia duration-dependent effects. All animals could bear weight on the affected limb to ambulate by 1 week posttreatment. Two-way analysis of variance (ANOVA) comparison of the resulting data confirmed a significant difference between control and ischemia-treated rabbits for: (1) vessel perfusion/reperfusion; (2) vessel caliber; and (3) net bone resorption. Vascular responses to 4 vs. 6 h of ischemia were not significantly different, but net bone resorption was strictly ischemia duration-dependent. The conclusion that reperfusion injury was the mechanism spreading ischemia to more vessels was supported by a decrease in reperfusion and caliber of vessels, and an increase in vascular permeability and leukocyte adherence during the reperfusion phase. It is postulated that reperfusion injury produces a secondary ischemia that amplifies the occlusion-created primary ischemia and, in the present work, may have been succeeded by progressive episodes of ischemia, similar to the infarction pattern of ischemic hearts.

Age- and sex-dependent cancellous bone changes in a 4000y BP population.

We studied cancellous bone loss in a 4000y BP population, using several methods designed to detect age-related changes, in order to investigate the pattern of cancellous bone loss in this ancient population and to compare the results deriving from different methods used on identical specimens. We used 10-mm sections of fourth lumbar vertebral bodies and left femoral necks of 18 individuals of both sexes with estimated ages from 20 to 60 years of a 4000y BP bronze-age population. Stereoscopic photographs were used for three-dimensional analysis and trabecular number (TN) counting. After embedding, the following parameters were measured in different image analysis systems using plane parallel block samples: bone mineral density (BMD) in water by DEXA, and by evaluation of standardized radiographic images; fractional bone volume (BV/TV) in backscattered electron images of the trabecular surface layer and in optical images of trabeculae in a surface-stained layer; and trabecular bone pattern factor (TBPf) in the latter images. There was a high correlation between the results of morphological methods for measuring fractional bone volume. Reasonable correlations were found between the x-ray photon methods and poor correlations between these and the morphological methods. These poor correlations may be due to the diagenetic substitution occurring in archaeological skeletons, which would strongly influence x-ray-based density measurements. However, all the methods demonstrated that the most dramatic loss of quantity and quality in cancellous bone occurred in females between 40 and 60 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast irradiation following silicone gel implants.

Little information is found in the literature regarding breast irradiation in patients with reconstructed or augmented breasts. From November 1970 to October 1984, we treated ten patients with silicone gel prostheses with external radiation for recurrent disease, or as primary therapy. All patients were treated with megavoltage equipment. Technique and doses varied with the clinical situation, but generally, patients received 5000 rad in five weeks to the breast or mound with opposed tangential fields. The majority of patients had excellent cosmetic results with minimal late skin changes and no fibrosis or contracture. We conclude that, with proper surgical and radiotherapeutic techniques, good cosmetic results can be obtained in these patients, without compromising their therapy.

Treatment-related morbidity in phase III RTOG studies of extended-field irradiation for carcinoma of the prostate.

The incidence, severity, time of onset, and clinical course of complications of treatment have been reviewed in the RTOG studies of extended field irradiation in carcinoma of the prostate. A total of 526 patients, entered between 1976 and 1980 and followed for a minimum of 18 months, comprised the study population. In most instances of treatment-related morbidity, the symptoms were recorded during the first several months to 1 year following completion of treatment. Late occurrences, however, were not uncommon in certain types of radiation-produced injuries, such as proctitis, hematuria, and urethral strictures. Resolution of symptoms has been observed in a large proportion of patients including those with late occurrences of treatment-related morbidity, although the probability and the pattern of resolution differed considerably from one type of morbidity to another. Symptoms of cystitis are more likely to abate than those of proctitis. In patients who develop symptoms of proctitis the probability of persistence of symptoms beyond the second year following occurrence has been estimated at 20%-30%. Hematuria and symptoms secondary to urethral strictures seem to be even more likely to recur or persist, while genital and leg edema remain chronic in the majority of patients.

Analysis of preoperative intracavitary cesium application versus postoperative external beam radiation in stage I endometrial carcinoma.

Two groups of patients with surgical Stage I endometrial carcinoma treated at the LDS Hospital in Salt Lake City are analyzed. Group 1 comprises 112 patients treated from 1974 through 1976, during which time preoperative intracavitary cesium was routinely used in all patients. Group 2 comprises 117 patients treated 1981 through 1983 under the treatment policy of hysterectomy without preoperative cesium. High risk patients from each group (grade 3 and/or deep myometrial invasion) generally received similar postoperative external beam pelvic radiotherapy (4500-5000 cGy). While 5-year actuarial disease-free survival rates were similar in each group (94% Group 1 vs 91% Group 2), multivariate analysis by the Cox Regression Method revealed that inclusion within treatment Group 2 carried independent adverse prognostic significance (p = 0.018). Other independent predictors of adverse 5-year disease-free survival included deep myometrial invasion and increasing histologic grade. Group 1 patients with grade 3 lesions had a superior 5-year actuarial disease-free survival (76% vs 53%) compared to those from Group 2. Group 1 patients with deep myometrial invasion also had a superior 5-year disease-free survival (84% vs 69%). The remaining low risk patients (grade 1 or 2, less than 1/3 myometrial invasion) had an excellent 5-year disease-free survival with or without preoperative cesium. Immediate preoperative intracavitary cesium was well tolerated, did not obscure pathologic findings and in our experience, reduced the probability of recurrence in high risk Stage I endometrial carcinoma patients.

New aspects of the degeneration of bioprosthetic heart valves after long-term implantation.

Bioprosthetic heart valves removed 76 to 150 months after implantation were morphologically investigated to correlate structural alterations with clinical failure modes. Traditional morphologic methods of evaluating valvular heterografts, such as microradiography and electron microscopy, were complemented by undecalcified ground sections, a new technique for analyzing the distribution of mineral deposits. Apart from well-investigated mechanisms that accelerate tissue degeneration, our observations point to additional facts: (1) phagocytosis of collagen fibrils and elastic material by macrophages and foreign body giant cells in areas near tears and perforations and (2) initial calcification indicated by delicate crystals in the intercellular space arranged in close relation to the periodicity of the cross-striation pattern of collagen fibrils. The present report not only calls attention to degenerative changes that are enhanced by mechanical stress but also underlines phagocytosis as an important mechanism in the destruction of bioprosthetic heart valves.

Experience with bioceramic implants in orthopaedic surgery.

In the period from 1974 to March 1980 bioceramic endoprostheses were implanted in 155 patients. 94 patients were suffering from degenerative hip diseases and 61 had been operated for malignant bone tumours. The majority of the total endoprostheses consisted of a ceramic socket and a metal shaft prosthesis with ceramic head attached to it. Bioceramic double-cup prostheses were implanted in 19 patients without using bone cement. Following resection of malignant bone tumours, the proximal humerus and the proximal femur were replaced by special bioceramic endoprostheses. The post-operation period after implantation has reached 70 months in the case of tumour endoprostheses (average 22 months) and up to 49 months in the case of hip joint endoprostheses (average 24 months). The analysis deals exclusively with complications specific to the ceramic material. These complications are: breakage of the ceramic head (8 X), loosening of the ceramic cup (13 X) and pseudarthrosis of the cone connection in tumour endoprostheses (9 X). Abrasion particles were found in all cases which we were able to follow up histologically.

Braided polypropylene augmentation device in reconstructive surgery of the anterior cruciate ligament: long-term clinical performance of 594 patients and short-term arthroscopic results, failure analysis by scanning electron microscopy, and synovial histomorphology.

Long-term clinical results and short-term arthroscopic and microscopic findings from two augmented reconstruction procedures for the ruptured anterior cruciate ligament are reported. The braided polypropylene ligament augmentation device (Kennedy model) was used with temporary double-end fixation in 279 patients to augment the attachment of the anterior cruciate ligament after acute proximal rupture and in 315 patients to augment a bone-tendon-bone autograft, mainly after chronic instability. Check arthroscopy was performed and the metal fixation hardware was removed after a mean of 11 months. Of the 569 patients evaluated, 101 partial or total breakages of the ligament augmentation device were found. Together with nine breakages detected late in the follow-up period, 110 (19.3%) failures were found. Most of these failures were accompanied by effusion that was immediately alleviated when the failed device was removed. No generalized synovitis was visible. Scanning electron microscopic analysis of 24 retrieved failed ligament augmentation devices showed fatigue to be the principal failure mode, together with local abrasion at the fracture. Synovial biopsies were taken during arthroscopy in 84 patients with and without ligament augmentation device-failure who had given informed consent, and histological evaluation revealed that in 21 patients, chronic but no acute synovial inflammation was found, and wear particles could be identified in foreign body cells in 17. Statistically, the presence of chronic synovitis was predicted neither by wear particles and foreign body cells nor by abrasion or fatigue failure of the ligament augmentation device. Irrespective of the failures, for which ligament augmentation device removal is recommended, in the final Orthopaedische Arbeitsgemeinschaft Knie evaluation (after a mean of 6.2 years), excellent and good clinical results were found in 83.6% of all 594 patients.

Effect of bone cylinder length on distraction osteogenesis in the rabbit tibia.

The viability and osteogenic potential of bone cylinders for bone transport was investigated in one tibia of 18 mature male New Zealand rabbits. The length of the bone cylinder was equal to or twice that of the diameter of the tibia. The cylinder was cut subperiosteally with an externally cooled oscillating saw from a lateral approach, after a specific unilateral external fixator had been applied. To simulate bone transport, one end of the cylinder was fixed to the distal bone stump by a cerclage wire and healing and revascularization was prevented by an interposed expanded polytetrafluoroethylene membrane. The periosteum was re-adapted and sutured, and distraction began 10 days postoperatively at 0.25 mm/12 hours for 22 days. New bone formation in the distraction gap was quantified by dual energy x-ray absorptiometry and by computer-assisted histomorphometry of polyfluorochrome-labeled undecalcified bone sections and corresponding microradiographs. In half of the animals with each size cylinder, osseous bridging occurred, so the findings on distraction osteogenesis are reported only for the remaining nine animals. Generally, centripetal mineralization of the gap with two distinct zones of ripening bone structures and a central radiolucent fibrocartilaginous zone could be distinguished. Neither absorptiometry nor histomorphometry showed significant differences in the overall amount of this new bone formation for the bone cylinders of two different lengths. However, osteogenesis was significantly greater at the proximal end than at the cylinder. New bone was formed predominantly from endosteal sites in the smaller cylinders and from periosteal sites in the larger cylinders. Histologically, there was complete necrosis of both sizes of cylinders, followed by revitalization through newly formed vascular channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Recorticalization after bifocal internal bone transport in the double-plated sheep femur.

Distraction osteogenesis and bone remodelling after the end of bone transport were investigated in one femur each of six adult male sheep. A newly designed internal distraction device was used. A custom-made osteosynthesis plate was fixed on the lateral side of the femur, and two transporting plates driven by a transcutaneously inserted screwdriver moved two bone cylinders simultaneously over a 40 mm defect. An additional plate was applied ventrally to stabilize the device. Bone transport was begun 2 weeks postoperatively at 1 mm/day at each transporting plate until they came into contact. New bone formation within the distraction gaps was evaluated by computed tomography scans and was quantified at 4 and 6 months by dual energy x-ray absorptiometry as well as histomorphometry on polyfluorochrome-labelled undecalcified ground sections and microradiographs. At 4 months, all distraction gaps were bridged by abundant newly formed bone trabeculae, which were reduced and condensed to cortex-like layers of new bone at 6 months. Less new bone was always found under the lateral device than in the unplated medical and dorsal segments, but the amount of new bone under the ventral plate was comparable with that in the unplated regions. The results of this pilot study show that distraction osteogenesis can be achieved with an internal device such as this one and that recorticalization and restoration of a medullary canal occur despite the relatively rigid internal stabilization by the plates.

Gross and microscopic histopathological findings in aneurysms of the human brain treated with Guglielmi detachable coils.

OBJECT: The histopathological characteristics of aneurysms obtained at autopsy or surgery 3 days to 54 months after being treated with Guglielmi detachable coils (GDCs) were assessed. METHODS: Seventeen aneurysms were obtained at autopsy and one was removed at surgery. Fourteen were examined histologically with the coils in situ. Naked coils embedded in an unorganized thrombus were found in those aneurysms that had been treated with coils within 1 week earlier. An incomplete replacement of the intraluminal blood clot by fibrous tissue and a partial membranous covering at the aneurysm orifice were observed in those aneurysms that had been treated with coils between 2 and 3 weeks prior to examination. One small aneurysm treated 6 weeks before harvesting showed formation of an endothelium-lined layer of connective tissue at the orifice. Collagen-rich vascularized tissue surrounding the coils was found in an aneurysm removed at surgery 54 months after coil implantation. Interestingly, six (50%) of 12 aneurysms (two small, three large, and one giant) that had been deemed 100% occluded on initial angiography showed tiny open spaces between the coils at the neck on gross examination. CONCLUSIONS: Endothelialization of the aneurysm orifice following placement of GDCs can occur; however, it appears to be the exception rather than the rule. In large aneurysms the process of intraaneurysm clot organization seems to be delayed and incomplete; tiny open spaces between the coils and an incomplete membranous covering in the region of the neck are frequently encountered. Further longitudinal studies are required to establish the spectrum of healing profiles that may direct our efforts in modifying the GDC system to produce a more stable long-term result.

2D-finite element analyses and histomorphology of lag screws with and without a biconcave washer.

For osteosynthesis and for bone transplant fixation in particular, a lag screw with a biconcave washer, the so called "Anchor Screw" (AS) has been introduced in maxillo-facial surgery. Using 2D-finite element analysis (FEA), the v. Mises and the circumferential stresses induced in underlying bone by this AS are analysed and compared to those under a conventional lag screw. The stress distributions below the biconcave washer of the AS were correlated with histomorphological bone reactions after AS osteosynthesis in two tumor patients, retrieved 12 weeks and 19 months after tumor surgery, respectively. Depending on the thickness of cortical bone, the v. Mises stress concentrations below the biconcave washer were lower than under the head of the conventional lag screw (CLS), but with a higher stress maximum concentrated around the rim of the washer. The circumferential stresses were only half as high around the AS, and thus the deformation of bone was reduced. As predicted by FEA, histology showed microcrack formation, but then after minimal resorption, remodelling of bone below the biconcave washer. Stable osteosynthesis could be demonstrated by bony union already after 12 weeks, and, while bone remodelling continued in the healed osteotomy, it had decreased around the screws after 19 months. It can be concluded from the biomechanical principles and the histomorphological findings that the AS appears superior to the CLS.

Preliminary report on phase III RTOG studies of extended-field irradiation in carcinoma of the prostate.

The radiation therapy oncology group (RTOG) has conducted two studies testing the value of extended-versus limited-fields in carcinoma of the prostate. RTOG protocol 75-06 tests the value of paraaortic irradiation in patients with locally advanced tumors limited to the pelvis. RTOG protocol 77-06 tests the value of pelvic irradiation in patients with tumors limited to the prostate. Two hundred sixty-eight evaluable patients have been entered on RTOG 75-06, and 219 on RTOG 77-06 prior to 1981. This is a preliminary report on treatment-related morbidity in patients followed for a minimum of 1 year. Treatment-related morbidity has been classified according to a five-grade severity classification schema and correlated with the protocol option assignment in order to determine whether the use of extended fields had an effect on the incidence of side effects. Thirty-one percent of 268 patients on RTOG 75-06 and 34% of 219 patients on RTOG 77-06 had some form of treatment side effects. The majority (over 80%) of these were mild (grade 1 and 2) and by definition did not interfere with the patients' performance (life style). Only three patients on RTOG 75-06 and one on RTOG 77-06 had grade 4 complications (by definition requiring a surgical intervention). No fatal (grade 5) complications have been recorded so far. The use of paraaortic fields in RTOG 75-06 and pelvic fields in RTOG 77-06 have not resulted in a significant increase of GI or GU morbidity at this time. The only statistically significant trend was the incidence of postirradiation genital and lower extremity edema which strongly correlated with the extent of staging lymphadenectomy.