One-step reconstruction with a 3D-printed, biomechanically evaluated custom implant after complex pelvic tumor resection.

Resection of a pelvic tumor is challenging because of its complex three-dimensional (3D) anatomy and deep-seated location with nearby vital structures. The resection is technically demanding if a custom implant is used for reconstruction of the bone defect as the surgeon needs to ensure the resection margin is sufficiently wide and the orientation of intended resection planes must match that of the custom implant. We describe a novel workflow of performing a partial acetabular resection in a patient with pelvic chondrosarcoma and reconstruction with a custom pelvic implant in a one-step operation. A multi-planar bone resection was virtually planned. A computer-aided design implant that both matched the bone defect and biomechanically evaluated was prefabricated with 3D printing technology. The 3D-printed patient-specific instruments (PSIs) were used to reproduce the same planned resection. The histology of the tumor specimen showed a clear resection margin. The errors of the achieved resection and implant position were deviating (1-4 mm) from the planned. The patient could walk unaided with a good hip function. No tumor recurrence and implant loosening were noted at 11 months after surgery. The use of this novel CT-based method for surgical planning, the engineering software for implant design and validation, together with 3D printing technology for implant and PSI fabrication makes it possible to generate a personalized, biomechanically evaluated implant for accurate reconstruction after a pelvic tumor resection in a one-step operation. Further study in a larger population is needed to assess the clinical efficacy of the workflow in complex bone tumor surgery.

Use of a patient-specific CAD/CAM surgical jig in extremity bone tumor resection and custom prosthetic reconstruction.

Computer navigation has recently been introduced for bone tumor surgery in the orthopedic field, with the aim of achieving increased accuracy and precision in tumor resection and in custom prosthetic reconstruction. However, the technique requires bulky navigation facilities, the presence of a system operator in the operating room, and surgeons with prior experience in navigated surgery. We describe a new and simple method of using a patient-specific computer-aided design/computer-aided modeling (CAD/CAM) surgical jig to realize the preoperative planning in the surgical field. The accuracy of the proposed method was first tested in a cadaver trial. It took one minute to set the location of the jig prior to the bone resection and three minutes to perform the bone resections via the cutting slits of the jig. The dimensional difference between the achieved and planned bone resection was <1 mm on validation with the help of a junctional plate and a navigation system. The technique was then applied successfully to a patient with a low-grade osteosarcoma of the femur. An intercalated tumor resection was performed using a patient-specific surgical jig, and a custom CAD prosthesis reconstruction matched accurately to the skeletal defect. Further assessment in a larger population is necessary to determine the clinical efficacy of the technique.

Integration of CAD/CAM planning into computer assisted orthopaedic surgery.

Modern Computer Aided Design/Modeling (CAD/CAM) software allows complex surgical simulations, but it is often difficult to transfer and execute precisely the planned scenarios during actual operations. We describe a new method of integrating CAD/CAM surgical plans directly into a computer surgical navigation system, and demonstrate its use to guide three complex orthopaedic surgical procedures: a periacetabular osteotomy of a dysplastic hip, a corrective osteotomy of a post-traumatic tibial deformity, and a multi-planar resection of a distal femoral tumor followed by reconstruction with a CAD custom prosthesis.

Navigation Endoscopic Assisted Tumor (NEAT) surgery for benign bone tumors of the extremities.

A novel technique of using both a navigation system and an endoscope in intra-lesional curettage of benign bone tumors enables safe and adequate tumor removal via a minimal access approach. We performed curettage of benign bone tumors in five consecutive patients (4 female, 1 male, mean age 31.4 years) using a commercial CT-based navigation system supplemented by visual guidance through a shoulder arthroscope. The bone defect was filled with bone cement in four patients and with artificial bone substitute in one patient. Mean follow-up time was 8.8 months (range: 7-12 months). Mean duration of surgery was 144 min (range: 120-165 min). Mean wound length of each portal site was 19.5 mm (range: 15-25 mm). All patients could achieve a full range of joint movement and walk unaided at 4 weeks post-surgery. No local recurrence was noted.

Ultrasound features of deep-seated lipomas.

PURPOSE: The objective of this study was to describe the sonographic features of deep-seated lipomas. METHODS: A retrospective review of the sonographic features of 64 deep seated lipomas in 64 patients (43 females, 21 males, mean age 46.5, range 16-77 years) seen over an 8-year period (1998-2006) was undertaken. RESULTS: Features evaluated were location, size, shape, marginal definition, internal echogenicity, including the presence of intermingled muscle fibres and linear internal echoes, acoustic transmission and vascularity. Confirmation was histological in 37 (58%) cases and by typical magnetic resonance imaging (MRI) appearance in 27 (42%) cases. CONCLUSION: The results show that although the features of deep-seated lipoma are more variable than those reported for subcutaneous lipomas, the presence of thin internal echoes in conjunction with other less specific features should enable a correct diagnosis.

Web-based formative assessment case studies: role in a final year medicine two-week anaesthesia course.

Formative Assessment Case Studies (FACS) are an e-learning resource consisting of a case scenario punctuated with decision-making steps (multiple-choice questions) and feedback for wrong answers. FACS was developed to enhance clinical decision-making skills. We wrote six FACS scenarios covering preoperative assessment topics and made them accessible to 149 final year medical students as part of their two-week anaesthesia module. A data management system recorded usage and performance by each student. Eighty-one percent of students attempted FACS (six cases 53%, five cases 17%, one to four cases 9%) and 61 to 70% completed all steps. On average FACS was attempted 1.5 times. Students required 44 to 95% more steps than the minimum to complete each case. There were two patterns of use: some students completed the cases within five to seven minutes (first quartile) focusing on the questions, while others spent over 22 to 35 minutes (fourth quartile) exploring the FACS and feedback. FACS usage correlated (r2 = 0.32: P < 0.01) with written case report marks. The students' evaluation of FACS was high. FACS is an e-learning resource that is interactive and facilitates higher learning. It can be applied successfully to disciplines less well represented in the medical curriculum, such as anaesthesia. FACS facilitated our teaching of preoperative assessment to a group of final year medical students. It was well received and shown to facilitate the learning of decision-making skills. The students' usage of FACS could have been enhanced by making FACS compulsory and using summative FACS for assessment.

Precision tumour resection and reconstruction using image-guided computer navigation.

The use of a navigation system in musculoskeletal tumour surgery enables the integration of pre-operative CT and MRI images to generate a precise three-dimensional anatomical model of the site and the extent of the tumour. We carried out six consecutive resections of musculoskeletal tumour in five patients using an existing commercial computer navigation system. There were three women and two men with a mean age of 41 years (24 to 47). Reconstruction was performed using a tumour prosthesis in three lesions and a vascularised fibular graft in one. No reconstruction was needed in two cases. The mean follow-up was 6.9 months (3.5 to 10). The mean duration of surgery was 28 minutes (13 to 50). Examination of the resected specimens showed clear margins in all the tumour lesions and a resection that was exactly as planned.

Primary osteochondrorhabdomyosarcoma (malignant mesenchymoma) of the fibula: a rare tumour in an unusual site -- case report and review of the literature.

Malignant mesenchymoma, defined by Stout as sarcomas comprising two or more unrelated differentiated tissue elements other than a fibrosarcoma component, is rare. We report a case of primary malignant mesenchymoma of the proximal fibula in a 10-year-old female student who presented with pain and swelling of the right knee for 2 months. Initial biopsy showed features of rhabdomyosarcoma only, but the resected specimen revealed additional osteosarcomatous and chondrosarcomatous elements. The patient remained well more than 5 years after initial presentation. Including our present patient, 16 cases of primary malignant mesenchymoma of bone are found in the English literature, affecting mainly adolescents and young adults, with a slight male predominance and predilection for the metaphysis of long bones, especially around the knee. More than 60% of the patients develop metastasis, almost invariably to the lung, but occasionally to the brain. About 60% of the patients, all with metastasis, died mostly within one year of diagnosis. The clinical features of primary malignant mesenchymoma of bone thus resemble those of conventional osteosarcoma. Moreover, our case illustrates that, with combination chemotherapy targeted for individual elements, the prognosis of this rare tumour might be much improved, as in osteosarcoma.

Papillary endothelial hyperplasia within synovial haemangioma of the flexor tendon sheath of the wrist.

A 60-year-old housewife presented with a painful and slowly enlarging swelling in the left wrist for 3 months. Plain X-ray showed mild soft tissue swelling and ultrasonography tenosynovitis of the flexor tendons. Exploration revealed a vascular growth involving the synovium of the flexor tendon sheath of the left little finger. Synovectomy and excision of the entire growth led to the diagnosis of synovial haemangioma with areas of recent haemorrhage and florid papillary endothelial hyperplasia. The recent haemorrhage corresponded to the sudden increase in size, while the papillary endothelial hyperplasia accounted for the persistence and gradual enlargement of the lesion. The patient made an uneventful recovery and remained well more than 2 1/2 years after the operation.

Alendronate regulates cell invasion and MMP-2 secretion in human osteosarcoma cell lines.

BACKGROUND: Osteosarcoma is the most common malignant bone tumor of childhood. Significant proportions of these patients eventually develop pulmonary metastases and succumb to their disease even after conventional multi-agent chemotherapy and surgical excision. Matrix metalloproteinase (MMP)-2 induced degradation of blood vessel basement membranes is an important pre-requisite for tumor invasion and metastasis. Bisphosphonates (BPs) have been known to inhibit tumor growth and metastasis in some tumors such as breast cancer, renal cell carcinoma, and prostate cancer, and may do so through inhibition of MMP secretion. We, therefore, tested the effect of BPs on tumor cell invasion, MMP-2 secretion, and apoptosis of osteosarcoma cell lines. PROCEDURE: Two osteosarcoma cell lines (SaOS-2, U(2)OS) were treated with alendronate (50, 100, and 150 microM) for 24 and 48 hr. Matrigel invasion assay was used to investigate the invasive potential of osteosarcoma cell lines before and after alendronate treatment. Real-time quantitative RT-PCR was used to determine the mRNA level of MMP-2 with and without alendronate treatment. Enzyme-linked immunosorbent assay (ELISA) was used to quantify the cytokine level of MMP-2 secreted in the condition medium. BP-induced cell apoptosis was evaluated by fluorescent flow cytometric analysis. RESULTS AND CONCLUSIONS: The results showed that alendronate inhibited cell invasion of both osteosarcoma cell lines in a dose-dependent manner. Alendronate reduced the mRNA level and cellular level of MMP-2 in both cell lines in a time and dose-dependent manner. Alendronate also induced significant apoptosis in both cell lines. Our finding suggests that alendronate downregulates MMP-2 secretion and induces apoptosis in osteosarcoma cells, which may both contribute to the reduction of invasive potential of the tumor cells.

Bisphosphonates induce apoptosis of stromal tumor cells in giant cell tumor of bone.

Giant cell tumour of bone (GCT) is an aggressive primary neoplasm that results in the production of osteolytic lesions. Stromal cells, which form the main neoplastic component of this tumor, regulate the formation of osleoclast-like giant cells that are ultimately responsible for bone destruction. Bisphosphonates prevent bone resorption by inhibiting osteoclast activity and promoting osteoclast apoptosis, and they have been known to induce apoptosis of primary neoplastic cells such as those in breast and prostate cancers. We hypothesized that in bisphosphonates may induce apoptosis not only in osteoclast-like giant cells but also in neoplastic stromal cells of GCT both in vitro and in vivo. Twelve patients with GCT were treated with weekly injections of pamidronate for a period of 6 weeks prior to surgery. GCT specimens were collected at the time of biopsy and during definitive surgery. TUNEL assay was used to evaluate apoptotic DNA fragmentation in cells. In addition, twelve GCT primary cultures from these patients were treated with zoledronate, pamidronate, or alendronate for 48 hours at different doses (3, 30, or 150 microM) and subjected to apoptosis assay by flow cytometry following fluorescent Annexin-V labeling. The results showed that pamidronate significantly induced apoptosis in both osteoclast-like giant cells and stromal tumor cells, in vivo. All three bisphosphonates caused substantial apoptosis of stromal tumor cells in cultures. Zoledronate was the most potent reagent, resulting in an average cell death of 27.41% at 150 microM, followed by pamidronate (22.23%) and alendronate (15.3%). Our observations suggest that these drugs may be considered as potential adjuvants in the treatment of GCT.

Does Doppler analysis of musculoskeletal soft-tissue tumours help predict tumour malignancy?

AIM: To investigate whether analysing vascularity of soft-tissue tumours on ultrasound assists differentiating benign from malignant tumours. MATERIALS AND METHODS: One hundred and forty-eight vascular soft-tissue tumours in 148 patients (88 males, mean age 45.6 years) were studied. Final diagnosis was established histologically in 95 (64%) of cases. For each tumour, three-colour Doppler imaging features (vascularity, vascular density, vascular organization) and 13 pulsed Doppler (spectral analysis) parameters were assessed. Data analysis was performed to isolate optimal discriminatory criteria for differentiating benign from malignant tumours. RESULTS: Significantly more benign soft-tissue tumours had an organized vascular pattern on colour Doppler imaging. If the vascular pattern is organized, this is a good indicator of tumour benignity. However, this pattern was apparent in less then one-third of the soft-tissue tumours. Benign tumours also had significantly higher minimum end diastolic velocity (EDVmin) and lower mean ratio of resistive index (RImean) than malignant soft-tissue tumours, though considerable overlap existed between the two groups. CONCLUSION: Colour Doppler imaging analysis of soft-tissue tumours is of limited value when differentiating benign from malignant tumours. If an organized vascular pattern is present, the tumour is more likely to be benign. Flow characteristics were not specific enough to be applicable in clinical practice.

Expression of preosteoblast markers and Cbfa-1 and Osterix gene transcripts in stromal tumour cells of giant cell tumour of bone.

In giant cell tumour of bone (GCT), mononuclear stromal cells, which represent the neoplastic component of this lesion, regulate the formation of multinucleated osteoclast-like giant cells which are the characteristic hallmark of this tumour. However, the origin of stromal tumour cells has not yet been clearly defined. In this study, we evaluated several osteoblast markers including collagen type I, bone sialoprotein (BSP), osteonectin and osteocalcin in GCT using immunohistochemical techniques. Amongst the 13 GCT specimens and 7 GCT stromal cell (GCTSC) cultures studied, majority of the GCTSC synthesized type I collagen, BSP and osteonectin proteins but did not produce the differentiated osteoblast marker, osteocalcin. We further examined the regulation of several important osteogenic genes such as Cbfa-1, osterix and osteocalcin, and regulation of ALP activity in GCTSC in culture by bone morphogenetic protein 2 (BMP-2). Real-time PCR analysis indicated that Cbfa-1, osterix and osteocalcin mRNA were present in primary cultures of GCTSC. The addition of BMP-2 upregulated Cbfa-1 and osterix gene expression within 12 h and the enhancement was still observed at 24 h. ALP activity was minimal in untreated GCTSC in cultures. The number of ALP-positive GCTSC was significantly increased following treatment with BMP-2 or combinations with beta-glycerophosphate and ascorbic acid. In contrast, BMP enhancement of osterix mRNA level and ALP activity was also seen in SaOS2 osteoblast-like cells, but not in the primary culture of normal human skin fibroblasts. In summary, our data suggest that GCT stromal tumour cells may have an osteoblastic lineage and retain the ability to differentiate into osteoblasts.

Primary sclerosing epithelioid fibrosarcoma of the sacrum: a case report and review of the literature.

Sclerosing epithelioid fibrosarcoma is a rare tumour characterised histologically by a predominant population of epithelioid cells arranged in strands and nests, embedded in a fibrotic and hyalinised stroma. It is a low grade tumour with an indolent course. A 48 year old woman presented with a painful swelling over her back for six months. Investigation and biopsy revealed features of sclerosing epithelioid fibrosarcoma involving the left half of the sacrum, left sacro-iliac joint, and posterior part of the left ilium. Preoperative radiotherapy and wide location excision of the tumour were followed by metastatic recurrence of the tumour in the lung and scalp six years after initial presentation. The tumour showed typical histology of sclerosing epithelioid fibrosarcoma. The radiological features confirmed its primary location in the sacrum. The patient declined chemotherapy and died of disseminated disease eight years after initial presentation. Review of the literature confirms the fact that sclerosing epithelioid fibrosarcoma, despite its low grade, is a clinicopathologically distinct tumour with full malignant potential, the recurrence, metastasis, and mortality rate being 48%, 60%, and 35%, respectively. Sclerosing epithelioid fibrosarcoma can occur as a primary bone tumour, the clinical behaviour of which is probably similar to its soft tissue counterpart.

The effect of hyaluronan on osteoblast proliferation and differentiation in rat calvarial-derived cell cultures.

Hyaluronan (or hyaluronic acid, HA) is an essential component of extracellular matrices. It interacts with other macromolecules and plays a predominant role in tissue morphogenesis, cell migration, differentiation, and adhesion. The cell signaling functions of HA are mediated through the CD-44 receptor and are dependent upon the molecular weight of the polymer. We hypothesized that an HA of appropriate molecular weight alone in optimal concentration may induce osteoblast differentiation and bone formation. Enzyme-digested calvarial-derived mesenchymal cells from 2-day-old newborn rats were cultured with the addition of HA of three different molecular weights (2300, 900, and 60 kDa). We added, 0.5, 1.0, and 2.0 mg/mL HA for each molecular weight to the medium at the first plating of cells. After 7 to 20 days in culture, cell proliferation and differentiation were evaluated by measuring thymidine incorporation, alkaline phosphatase activity, and osteocalcin gene expression. The effects of HA on bone formation were examined by using Alizarin red staining for mineralization. The results showed that low molecular weight HA (60 kDa) significantly stimulated cell growth, increased osteocalcin mRNA expression in a dose-dependent manner, but showed no apparent effects on alkaline phosphatase activity and bone mineralization. On the other hand, high-weight HA (900 and 2,300 kDa) significantly increased all the parameters examined, particularly alkaline phosphatase activity, in a dose-dependent manner and stimulated cell mineralization to 126% and 119% of the controls, respectively, in the 1.0 mg/mL dose. Our findings suggest that HA has a molecular weight-specific and dose-specific mode of action that may enhance the osteogenic and osteoinductive properties of bone graft materials and substitutes due to its stimulatory effects on osteoblasts.

Expression of VEGF and MMP-9 in giant cell tumor of bone and other osteolytic lesions.

This study aims to investigate the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) in giant cell tumor of bone (GCT) and other osteolytic lesions in bone. By using semi-quantitative RT-PCR, we showed that three major isoforms of VEGF (121, 165 and 189) were expressed in GCTs, with isoform 121 being the most abundant. The expression levels of VEGF and MMP-9 mRNA were significantly higher in advanced GCTs (stage II/III) than in stage I GCTs. We further elucidated the cellular localization of VEGF and MMP-9 gene transcripts in GCT and other osteolytic lesions using an in situ hybridization assay. The results showed that stromal tumor cells and osteoclast-like giant cells of GCT, fibrous stromal cells in anuerysmal bone cysts and fibrous dysplasia, and Langerhans-type giant cells as well as histocytes in eosinophillic granuloma, were all strongly positive for VEGF and MMP-9 mRNA expression. In a prospective study, we performed VEGF and MMP-9 immuno-staining on paraffin sections of pathological tissues harvested from 48 patients (14 GCT, 10 anuerysmal bone cysts, 10 eosinophillic granuloma, 4 fibrous dysplasia, 2 simple bone cyst, 2 osteomyelitis and 6 patients with fractured femoral head as control). The results showed that the differences in VEGF and MMP-9 expression between Stage I and other advanced Stages (II, III and recurrent) were highly significant (p<0.001), with advanced stages showing a higher mean expression. The difference between recurrent and Stage II and III lesions, was also statistically significant (p=0.03 for VEGF, and p=0.01 for MMP-9 expression), with recurrent lesions showing a higher mean expression of both VEGF and MMP-9. In conclusion, VEGF and MMP-9 expression in osteolytic lesions of bone co-relates well with the extent of bone destruction and local recurrence. Their expression may therefore provide some prognostic indication of the possible aggressive behavior of the underlying pathology.

Local flap coverage for soft tissue defects following open repair of Achilles tendon rupture.

The authors assessed the long term clinical and functional results following local flap coverage (medial plantar flap, peroneal reverse flow island flap, posterior tibial reverse flow flap) in 11 patients who developed wound complications after open repair of a ruptured Achilles tendon. At the latest follow-up, seven patients had achieved a good result, having returned to their pre-injury activities. All patients were able to stand on tiptoes unaided, and were able to walk without aid. In our hands, local flaps are a reliable means of treating skin defects following open repair of subcutaneous ruptures of the Achilles tendon.

Receptor activator of NF-kappaB ligand (RANKL) is expressed in chondroblastoma: possible involvement in osteoclastic giant cell recruitment.

AIMS: Chondroblastoma is a rare, locally aggressive bone tumour that causes osteolytic destruction at the epiphyseal end of the affected bone. It is possible that tumour cells may stimulate osteoclastogenesis and osteolytic destruction through the production of receptor activator of NF-kappaB ligand (RANKL), which is a key molecule essential for regulating osteoclast formation and activity. Therefore, the expression of RANKL at both the mRNA and the protein level was investigated in chondroblastoma tumour tissue obtained from patients. METHODS: The expression of RANKL gene transcripts was analysed by the reverse transcription-polymerase chain reaction (RT-PCR), and the cellular localisation of RANKL mRNA and protein was demonstrated by means of in situ hybridisation and immunohistochemistry. RESULTS: RT-PCR analysis indicated that RANKL mRNA was present in all chondroblastoma specimens and normal cancellous bone samples, but not in normal articular cartilage and chondrosarcoma tissues. In contrast, gene transcripts of osteoprotegerin (OPG), the decoy receptor of RANKL, were detected in all types of tissues. The chondroid origin of neoplastic mononuclear cells in chondroblastoma was confirmed by positive S-100 immunohistochemical staining. Both RANKL mRNA and protein were exclusively expressed in these neoplastic mononuclear cells. CONCLUSIONS: These findings suggest that RANKL may be involved in the tumour cell induced recruitment of osteoclast-like cells and consequent osteolytic bone destruction in chondroblastoma.

Massive intestinal hemorrhage resulting from a polypoid tumor in the sigmoid colon: an unusual complication of a giant cell tumor of the fifth lumbar vertebra.

STUDY DESIGN: Clinicopathologic study of a case of giant cell tumor of the spine. SUMMARY OF BACKGROUND DATA: Giant cell tumors of the spine are uncommon, accounting for 1.3-6.5% of all cases in various series. Because of their location, they may cause neurologic deficits. The treatment consists of excision or curettage and has been claimed to give good results. METHODS: A 33-year-old woman presented with low back pain in 1995; radiologic investigation and biopsy showed features of giant cell tumor involving the fifth lumbar and first sacral vertebrae. Wide excision was performed, but the tumor recurred in 1996 and was curetted. She developed massive intestinal bleeding in 1997 resulting from infiltration of the sigmoid colon by giant cell tumor in the form of a polypoid intraluminal mass. The involved segment of colon was resected, and the patient remained alive, although debilitated, 7 years after initial presentation. RESULTS: Examination of the tumor in the spine and the colon showed typical histology of giant cell tumor with no evidence of malignant transformation. The involved colon was freely mobile and away from the tumor of the spine. CONCLUSION: Giant cell tumor of the spine can result in unusual complication, massive intestinal hemorrhage in our case, which causes considerable morbidity.