Development and external validation of a machine learning model for prediction of survival in undifferentiated pleomorphic sarcoma.

PURPOSE: Machine learning (ML) algorithms to predict cancer survival have recently been reported for a number of sarcoma subtypes, but none have investigated undifferentiated pleomorphic sarcoma (UPS). ML is a powerful tool that has the potential to better prognosticate UPS. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for cases of histologically confirmed undifferentiated pleomorphic sarcoma (UPS) (n = 665). Patient, tumor, and treatment characteristics were recorded, and ML models were developed to predict 1-, 3-, and 5-year survival. The best performing ML model was externally validated using an institutional cohort of UPS patients (n = 151). RESULTS: All ML models performed best at the 1-year time point and worst at the 5-year time point. On internal validation within the SEER cohort, the best models had c-statistics of 0.67-0.69 at the 5-year time point. The Multi-Layer Perceptron Neural Network (MLP) model was the best performing model and used for external validation. Similarly, the MLP model performed best at 1-year and worst at 5-year on external validation with c-statistics of 0.85 and 0.81, respectively. The MLP model was well calibrated on external validation. The MLP model has been made publicly available at https://rachar.shinyapps.io/ups_app/ . CONCLUSION: Machine learning models perform well for survival prediction in UPS, though this sarcoma subtype may be more difficult to prognosticate than other subtypes. Future studies are needed to further validate the machine learning approach for UPS prognostication.

Bioceramic bone graft substitute for treatment of unicameral bone cysts.

PURPOSE: To review the outcome of 12 patients who underwent debridement and injection of bioceramic for unicameral bone cyst (UBC). The resorption rate of the bioceramic was estimated by both traditional and novel methods. METHODS: Records of 10 males and 2 females aged 6 to 34 years who underwent debridement and injection of bioceramic for UBC and were followed up for a mean of 41 (range, 26-57) months were reviewed. Functional outcome was assessed using the selfcompleted Musculoskeletal Tumor Society (MSTS) questionnaire. Radiological outcome was assessed using both original and modified Neer Outcome Rating System. The resorption rate of the bioceramic was estimated using both traditional and novel (ImageJ) methods. RESULTS: The mean MSTS score was 29.7 (range, 28-30) indicating excellent functional outcome. Of the 12 patients, 9 achieved complete healing and 3 had a residual cyst of 1%, 11%, and 52%. The last was considered a local recurrence, and the patient underwent repeat percutaneous injection of the bioceramic 1.5 years later and remained disease-free 4 years later. The mean resorption rate was 29% faster when estimated using the traditional rather than the ImageJ method (0.47 vs. 0.33 cm3/day, p=0.02). In the patient with recurrence, the resorption rate was faster than the average (0.68 vs. 0.33 cm3/day). CONCLUSION: A single percutaneous injection of the bioceramic for UBC achieved good functional and radiological outcome while avoiding donor-site morbidity.

Adamantinoma of the long bones. The experience at the Istituto Ortopedico Rizzoli.

All cases of adamantinoma seen at the Istituto Ortopedico Rizzoli were retrospectively reviewed. Although this tumor is exceedingly rare, nine cases were collected. The tumor is composed of four histological patterns: spindle, basaloid, squamoid, and tubular. The prognosis of this tumor depends on the adequacy of therapy. Surgery that is expedient and adequate tends to offer the best prognosis.

Partial deletions of the CDKN2 and MTS2 putative tumor suppressor genes in a myxoid chondrosarcoma.

Cytogenetic abnormalities of chromosome 9 (9p21) have been reported in a large number of tumors that include malignant melanomas, gliomas, lung cancers and leukemias. These aberrations on 9p have been previously shown to involve the loss of the interferon gene cluster and the gene for methylthioadenosine phosphorylase (MTAP), both of which have been mapped to the 9p21 region. Recently, two putative tumor suppressor gene(s) CDKN2 and MTS2, have been mapped to the 9p21 region, and have been shown to be deleted in a large number of hematopoietic and solid malignancies. In this study we report a cytogenetic and a detailed molecular analysis of a myxoid chondrosarcoma cell line 105KC and its clonal derivatives 105AJ, 105AJ1.1, 105AJ3.1, and 105AJ5.1. Specifically, we have demonstrated chromosome 9p21 related abnormalities by cytogenetic analysis, the associated loss of the interferon gene cluster, and the loss of the immunoreactive MTAP protein and activity. In addition, we have also shown the presence of deletions involving the CDKN2 and the MTS2 putative tumor suppressor genes in these chondrosarcoma cell lines. The above studies were extended to other chondrosarcoma cell lines and primary tumors, where similar deletions of the CDKN2 and MTS2 genes were found to be present (unpublished data). This suggests a potential role for the involvement of the CDKN2 and MTS2 putative tumor suppressor genes in the development of chondrosarcomas.

Chromosome 9 related aberrations and deletions of the CDKN2 and MTS2 putative tumor suppressor genes in human chondrosarcomas.

Deletions on the short arm of chromosome 9 (9p21 region) have been reported in a number of hematopoietic and solid tumors. These aberrations on 9p have been previously associated with the loss of the interferon gene cluster and the gene for methylthioadenosine phosphorylase (MTAP), localized to the 9p21-22 region. Recently, two putative tumor suppressor gene(s) CDKN2 and MTS2 have been mapped to the 9p21 region, and shown to be deleted in a large number of tumors including leukemias, melanomas, bladder cancers and brain tumors. We have previously reported a similar 9p21 abnormality and deletions of the CDKN2 and MTS2 genes in a myxoid chondrosarcoma cell line and its subclones. In this study we report consistent abnormalities of chromosome 9 in additional chondrosarcomas examined by a detailed cytogenetic and molecular analysis. Seven chondrosarcoma cell lines, one primary chondrosarcoma, and a benign chondroma were examined. Four of the seven tumor cell lines examined showed grossly visible aberrations of chromosome 9. Molecular analysis of these chondrosarcoma cell lines revealed hemizygous deletions of the interferon genes, and the absence of the MTAP gene, protein or activity. In addition, four of the seven chondrosarcoma cell lines also showed deletions of the CDKN2 and/or MTS2 putative tumor suppressor genes, or the absence of the CDKN2 protein product. No such chromosome 9 related aberrations were detected in the benign chondroma. These data suggest that chromosome 9p21 abnormality, and deletions of the CDKN2 and MTS2 tumor suppressor genes may be a significant event in the development of chondrosarcomas.

Chondrosarcoma of bone. The experience at the Istituto Ortopedico Rizzoli.

We retrospectively reviewed the records of 125 patients with chondrosarcoma seen at the Istituto Ortopedico Rizzoli. All of the patients had been followed for at least five years, and ninety-six patients had been followed for at least ten years. The requirements for the adequacy of treatment were carefully defined. Metastasis and survival were related to the histological grade of the tumor. Nine per cent of the grade-1 lesions and 44 per cent of the grade-3 lesions metastasized. Ninety-four per cent of the patients with grade-1 lesions survived for five years, compared with only 44 per cent of patients with grade-3 lesions. The ten-year survival rates were 87 per cent and 27 per cent, respectively. Adequacy of treatment had an important influence on the incidence of recurrence, length of survival, and length of disease-free survival. The incidence of recurrence in adequately treated patients was 6 per cent, but in inadequately treated patients it was 69 per cent. The five-year survival rates in these two groups were 81 per cent and 53 per cent, respectively. Seventy-eight per cent of the adequately treated patients were disease-free at follow-up (mean, 11.1 years) compared with only 6 per cent of the inadequately treated patients. We compared the results of this review with those of other reviews of chondrosarcoma.

Synthesis of chondrocytic keratan sulphate-containing proteoglycans by human chondrosarcoma cells in long-term cell culture.

Keratan sulphate is an integral component of the large aggregating proteoglycans of mature human articular cartilage. The keratan sulphate content of chondrocytic proteoglycans increases during maturation, and it is a useful marker of mature-type chondrocytic proteoglycans. Ordinarily, in cell culture, chondrocytes from non-neoplastic tissues dedifferentiate, diminish or cease to synthesize aggregating proteoglycans with the same amount of keratan sulphate as those formed in vivo, and do not maintain their in vivo phenotype. In tissue culture, this down-regulation of synthesis of keratan sulphate is irreversible. The study of the metabolism of mature human chondrocytes has been hampered by the absence of stable models. We report a cell-line, 105KC, derived from a human chondrosarcoma, that has maintained a stable proteoglycan phenotype during more than three years of culture. Analysis with immunofluorescence suggested that 105KC cells continued to synthesize keratan sulphate in long-term culture. Biochemical analysis demonstrated that 105KC cells maintained the production of chondrocytic large-aggregating proteoglycans and that keratan sulphate composed 13 per cent of their glycosaminoglycan content. To our knowledge, 105KC represents the first model to have maintained the post-fetal chondrocytic proteoglycan phenotype in stable culture. This study documents the feasibility of the development of mature chondrocytic cell-lines and sheds light on the biological characteristics of chondrosarcomas.

Function after amputation, arthrodesis, or arthroplasty for tumors about the knee.

We studied the function of twenty-two patients who had had a malignant skeletal tumor adjacent to the knee. An above-the-knee amputation was done in seven; a resection arthrodesis, in nine; and a replacement arthroplasty, in six. The patients all walked at a similar speed (sixty-one to sixty-six meters per minute), which is slower than normal (eighty meters per minute). They all walked with comparable efficiency at three velocities: the mean consumption of oxygen was 0.210 milliliter per kilogram of body weight per meter at free velocity, 0.215 milliliter per kilogram of body weight per meter when they walked 25 per cent faster, and 0.211 to 0.240 milliliter per kilogram of body weight per meter when they walked 50 per cent faster. The three groups of patients and a normal control group consumed oxygen at similar rates. The patients who had had an amputation were very active, and they were the least worried about damaging the affected limb, but they had difficulty walking on steep, rough, or slippery surfaces. The patients who had had an arthrodesis had a more stable limb and performed the most demanding physical work and recreational activities, but they had difficulty sitting. The patients who had had an arthroplasty led sedentary lives and were the most protective of the limb, but they were the least self-conscious about the limb.

Current trends in the management of adamantinoma of long bones. An international study.

BACKGROUND: Adamantinoma of long bones is a rare tumor. Published reviews of the orthopaedic management of adamantinoma have involved limited follow-up of small numbers of patients. The oncological aggressiveness of this tumor is unknown. Limb salvage is currently the treatment of choice for most adamantinomas. The purpose of this study was to evaluate the characteristics of adamantinoma of long bones as well as the oncological outcome and the complications of limb salvage operations. METHODS: A retrospective study was designed to evaluate the clinical outcomes of limb salvage operations for the treatment of adamantinoma. Data on seventy biopsy-proven cases of adamantinoma treated between 1982 and 1992 at twenty-three different cancer centers in Europe and North America were obtained. RESULTS: The median duration of follow-up was 7.0 years. The male:female ratio was 3:2, and the mean age was thirty-one years. Limb salvage was attempted in 91 percent (sixty-four) of the seventy patients, and the final rate of limb preservation was 84 percent (fifty-nine of seventy). Wide operative margins were obtained in 92 percent (fifty-eight) of sixty-three patients. An intercalary allograft was used to reconstruct the segmental bone defect in 51 percent (thirty-six) of the seventy patients. Reconstruction-related complications occurred in 48 percent (thirty) of sixty-two patients. Nonunion and fracture were the most common complications, occurring in 24 percent (fifteen) and 23 percent (fourteen) of sixty-two patients, respectively. Kaplan-Meier analysis demonstrated a rate of local recurrence of 18.6 percent at ten years. Wide operative margins were associated with a lower rate of local recurrence than marginal or intralesional margins were (p < 0.00005). Kaplan-Meier analysis showed a survival rate of 87.2 percent at ten years. There were no significant relationships between survival and the stage of the tumor (p = 0.058), duration of symptoms (p = 0.90), gender (p = 0.79), or wide operative margins (p = 0.14). CONCLUSIONS: Current treatment of adamantinoma, including en bloc tumor resection with wide operative margins and limb salvage, provides lower rates of local recurrence than has been previously reported. In the present study, the limb preservation rate was 84 percent (fifty-nine of seventy), and the survival rate was 87.2 percent at ten years. The rate of complications related to the limb reconstruction was high.

Intralesional excision compared with en bloc resection for giant-cell tumors of bone.

We reviewed the results for forty consecutively seen patients, each of whom had been managed by one surgeon for a giant-cell tumor of bone in an extremity between 1976 and 1990. Twenty patients had been managed with an en bloc resection and twenty, with an intralesional excision of the tumor with adjunctive local insertion of methylmethacrylate or phenol. All patients had been followed for a minimum of two years. Both en bloc resection and intralesional excision were found to be excellent oncological procedures. There were fewer complications and better functional results after the intralesional procedure than following the en bloc resection.

Osteosarcomas arising on the surfaces of long bones.

Malignant bone-forming tumors that arise from the surfaces of long bones are far less common than those that arise from within bone. These surface osteosarcomas are clinically and radiographically similar, yet histologically they are quite distinct. In reviewing the literature, we classified the tumors according to three subgroups: parosteal (juxtacortical) osteosarcoma, periosteal osteosarcoma, and high-grade surface osteosarcoma. We also studied the clinical, radiographic, and histological findings in eighty patients who had been treated for an osteosarcoma over a forty-four-year period. Adequate follow-up data existed for forty-eight of the eighty patients. The duration of follow-up ranged from two to fifteen years after the initial operation (amputation or resection). Patients who had a parosteal osteosarcoma had the best prognosis; those who had a periosteal osteosarcoma, the next best; and those who had a high-grade surface osteosarcoma, the poorest. Because of these widely varying prognoses, the lesions require different treatment.

Arthroplasty with a composite of an allograft and a prosthesis for knees with severe deficiency of bone.

We reviewed the clinical and radiographic results of fourteen patients who had a severe deficiency of bone and were managed with a massive allograft in conjunction with a standard total knee prosthesis between 1987 and 1990. The etiology of the bone loss included the failure of a previous total knee prosthesis, a supracondylar fracture of the femur or a fracture of the proximal part of the tibia, and débridement during the first stage of a reconstruction for the treatment of an infection. Thirteen patients had satisfactory clinical and radiographic results after the index procedure. The knee score of The Hospital for Special Surgery improved from an average of 24 points (range, 0 to 54 points) preoperatively to 82 points (range, 37 to 98 points) at the time of the most recent follow-up examination. The average duration of follow-up was forty-three months (range, twenty-nine to sixty-three months). The radiographic and functional results compare favorably with those that have been reported in most studies of otherwise comparable patients who had less deficiency of bone. While considerable risks are associated with the use of allograft bone and the true longevity of reconstructions with such bone is not yet known, the initial and short-term follow-up results support the use of allograft for the restoration of a functional knee joint in a patient who has a severe deficiency of bone.

Second-generation cementless total hip arthroplasty. Eight to eleven-year results.

BACKGROUND: Second-generation cementless femoral components were designed to provide more reliable ingrowth and to limit distal osteolysis by incorporating circumferential proximal ingrowth surfaces. We examined the eight to eleven-year results of total hip arthroplasty with a cementless, anatomically designed femoral component and a cementless hemispheric acetabular component. METHODS: Ninety-two consecutive primary total hip arthroplasties with implantation of a femoral component with a circumferential proximal porous coating (Anatomic Hip) and a cementless hemispheric porous-coated acetabular component (Harris-Galante II) were performed in eighty-five patients. These patients were prospectively followed clinically and radiographically. Six patients (seven hips) died and five patients (seven hips) were lost to follow-up, leaving seventy-four patients (seventy-eight hips) who had been followed for a mean of ten years (range, eight to eleven years). The mean age at the time of the arthroplasty was fifty-two years. RESULTS: The mean preoperative Harris hip score of 51 points improved to 94 points at the time of final follow-up; 86% of the hips had a good or excellent result. Thigh pain was reported as mild to severe after seven hip arthroplasties. No femoral component was revised for any reason, and none were loose radiographically at the time of the last follow-up. Two hips underwent acetabular revision (one because of dislocation and one because of loosening). Kaplan-Meier survivorship analysis was performed with revision or loosening of any component as the end point. The ten-year survival rate was 96.4% +/- 2.1% for the total hip prosthesis, 100% for the femoral component, and 96.4% +/- 2.1% for the acetabular component. Radiolucencies adjacent to the nonporous portion of the femoral component were seen in sixty-eight (93%) of the -seventy-three hips with complete radiographic follow-up. Femoral osteolysis proximal to the lesser trochanter was noted in four hips (5%). No osteolysis was identified distal to the lesser trochanter. Periacetabular osteolysis was identified in twelve hips (16%). Five patients underwent exchange of the acetabular liner because of polyethylene wear. CONCLUSIONS: This second-generation cementless, anatomically designed femoral component provided excellent clinical and radiographic results with a 100% survival rate at ten years. The circumferential porous coating of this implant improved ingrowth and prevented distal osteolysis at a mean of ten years after the arthroplasty.

Early failure of acetabular components inserted without cement after previous pelvic irradiation.

The effect of previous irradiation of the pelvis on the survival of acetabular components inserted without cement in primary total hip arthroplasty was examined. We searched a database of 1319 patients who had been managed with a primary total hip arthroplasty with insertion of a hemispherical porous-coated acetabular component without cement. This revealed twelve hips in eleven patients who had been managed with previous irradiation of the pelvis. Three patients had died after less than one year of follow-up, leaving eight patients with nine acetabular components available for study at an average of thirty-seven months (range, seventeen to seventy-eight months) after the operation. The type of radiation as well as the fractionation, dose, and portals were reviewed to determine the exposure of the periacetabular region to radiation. Failure of the component was assessed radiographically and clinically. At the time of follow-up, three of the nine acetabular components had migrated, as seen on radiographs, and had been associated with progressive radiolucency without clinical symptoms. Thus, four of the nine acetabular components failed, at an average of twenty-five months (range, sixteen to thirty-eight months). The other five components had not failed clinically and were stable radiographically at an average of thirty-six months (range, seventeen to sixty-three months). The insertion of acetabular components without cement in a previously irradiated pelvis has a high rate of failure. However, a superior method of acetabular reconstruction in this difficult situation has yet to emerge.

Early sarcomatous degeneration near a cementless hip replacement. A case report and review.

We present the case of a 65-year-old man who developed a malignant fibrous histiocytoma at the lesser trochanter five months after a cementless hip replacement. We have reviewed reports of similar cases and discuss them in terms of the possible mechanisms of sarcomatous degeneration and the latency of such changes.

Cartilage tumors: evaluation and treatment.

The proper treatment of cartilaginous tumors is dependent on the clinicopathologic and radiologic findings. Enchondroma is a benign tumor that is usually asymptomatic and thus should be treated nonoperatively. Symptomatic enchondromas are often treated by intralesional excision. Intramedullary low-grade chondrosarcoma is a malignant tumor that is usually painful. The treatment of low-grade chondrosarcoma may range from intralesional excision with or without adjuvant therapy to wide excision. Although intralesional excisions have a higher bone and joint preservation rate than wide excisions, they may be associated with a higher local recurrence rate. Intermediate- and high-grade chondrosarcomas are treated with wide excisions. The treatment of these cartilaginous lesions should involve a multidisciplinary team including a musculoskeletal surgeon, a radiologist, and a pathologist.

Osteoid osteoma and osteoblastoma.

In conclusion, while similar histologically, osteoid osteoma and osteoblastoma have the potential of being significantly different clinically. Osteoid osteoma tends to be a problem of pain and not of great oncologic significance. Osteoblastoma, on the other hand, has the potential for local bone destruction and aggressiveness as well as the rare occurrence of metastases. For this reason, the latter tumor needs to be respected from an oncologic standpoint and appropriate surgical excision performed.

The role of prophylactic surgery in the management of metastatic hip disease.

The surgical stabilization of pathological fractures has been advocated as early as 1953 as the best form of management for this difficult problem. The treatment of impending fractures has also been advocated, although the advantages of this form of treatment has not been clearly demonstrated in the literature. A consecutive series of 99 hips treated for a pathological fracture or an impending fracture of the hip were retrospectively reviewed. The patients treated prophylactically for an impending fracture had fewer complications, a löwer postoperative mortality rate, a lesser incidence of failure of stabilization, and a greater percentage of postoperative ambulators. Survival was not improved by prophylactic surgery. Adjunctive methyl methacrylate improved fixation and decreased the incidence of failure of stabilization of both impending and pathological fractures.

Use of a calcium sulfate-based bone graft substitute for benign bone lesions.

Twenty-three patients with a benign bone lesion grafted with calcium sulfate, with and without demineralized bone matrix, were reviewed. At a minimum of 1 year postoperatively, 21 patients had achieved between 76% and 100% bone repair based on anteroposterior and lateral radiographs. Overall, the mean Enneking Functional Evaluation System score was 98%. Calcium sulfate is a well-tolerated, biodegradable, osteoconductive bone graft substitute. It is a reasonable alternative to autogenous bone graft for benign bone lesions.

The use of a closed expandable prosthesis for pediatric sarcomas.

PURPOSE: The purpose of this paper is to review our experience with a non-invasive expandable prosthesis for skeletally immature patients following limb-salvage for malignant tumors about the knee. MATERIALS & METHODS: Between 1998 and 2002, Repiphysis prostheses (Wright Medical Technology, Memphis, Tenn.) were implanted in 18 patients. 16 patients had at least 12 months follow-up. There were 10 males and 8 females. The diagnosis was Stage IIB osteosarcoma in all patients. Sites included femur 14, and 4 proximal tibias. The average age was 10.7 years (range 8-16); the average age for males was 12 years and females, 9 years. Fifteen of the prostheses were implanted at the time of surgical resection and the remainder was conversions of previous surgery. RESULTS: Follow-up averaged 24.8 months (range 12-47). Fourteen patients have undergone a total of 58 lengthening procedures. Average expansion 38 mm per patient (range, 10-76 mm). An average of 8.5 mm per lengthening procedure. There was only one failure to lengthen. ISOLS functional scores averaged 83.5%. For those with a current functional prosthesis, the ISOLS score averaged 94%. Three patients have reached maximal expansion and converted to a conventional prosthesis. There were complications in 7 patients: 2 expandable component fractures, 1 femoral component fracture, 2 stem fractures, 1 stem loosening and 1 deep infection. Of the two expandable component fractures, 1 patient reached full expansion and was converted to an endoprosthesis. The femoral component fracture and 2 stem fractures were revised to a new prosthesis 13 months post-op and are functioning well. The 1 loose stem was revised to an APC. CONCLUSIONS: The Repiphysis prosthesis utilizes energy stored in a spring that is held compressed by a locking mechanism. Controlled release of the locking mechanism via an external electromagnetic field allows for lengthening of the device. In our early experience, the functional results were excellent similar to conventional modular devices. Complications should be anticipated but are salvageable. This device allows limb salvage in pediatric patients when amputation would be otherwise chosen.