Bone cysts in patients with afibrinogenaemia: a literature review and two new cases.

Afibrinogenaemia is an autosomal recessive disease with an estimated prevalence of approximately one in a million. The most common symptoms of afibrinogenaemia are umbilical cord bleeding, bleeding into skin, mouth, muscles, gastrointestinal and genitourinary tracts and the central nervous system. Other recognized complications include; haemarthroses, spontaneous splenic rupture, epistaxis, menorrhagia, recurrent abortion and venous and arterial thromboembolism. Bone cysts have also been described as a rare complication of afibrinogenaemia. The aim of this study was to conduct a systematic literature review, summarize the reported cases and to report two new cases. Three electronic databases were searched for relevant publications: PubMed, Medline and EMBASE. The following search criteria were used: '(bone cysts OR intraosseous haematoma OR intraosseous haemorrhage) AND (afibrinogenaemia OR fibrinogen deficiency)'. The reference lists of the selected papers were searched for more relevant literature. In total, eight patients had bone cysts as complication of afibrinogenaemia and six of them suffered from pain in their extremities. Bone cysts were primarily located in the vicinity of the cortex or trabeculae in the diaphysis of the long bones, especially in the femora, tibiae and humeri. Some were regressive, probably due to reactive bone remodelling. A number of cysts were filled with serosanguinous fluid. It might be useful to check for bone cysts when patients with congenital afibrinogenaemia complain of 'rheumatic' pains in their extremities. Whole body magnetic resonance imaging is the diagnostic imaging technique of choice. Recurrent episodes of pain, but not radiological deterioration, appear to benefit from prophylactic therapy with fibrinogen concentrate.

Giant cell tumors of the sacrum--a nationwide study on midterm results in 26 patients after intralesional excision.

PURPOSE: Evaluation of recurrences, complications and function at mid-term follow-up after curettage for sacral giant cell tumor (GCT). METHODS: We retrospectively studied all 26 patients treated for sacral GCT in the Netherlands (from 1990 to 2010). Median follow-up was 98 (6-229) months. All patients underwent intralesional excision, 21 with local adjuvants, 5 radiotherapy, 3 IFN-α, 1 bisphosphonates. Functional outcome was assessed using Musculoskeletal Tumor Society (MSTS) score. Statistics were performed with Kaplan-Meier, Cox regression, log rank and Mann-Whitney U. RESULTS: Recurrence rate was 14/26 after median 13 (3-139) months and was highest after isolated curettage (4/5). Soft tissue masses >10 cm increased recurrence risk (HR = 3.3, 95 % CI = 0.81-13, p = 0.09). Complications were reported in 12/26 patients. MSTS was superior in patients without complications (27 vs. 21; p = 0.024). CONCLUSION: Recurrence rate for sacral GCT was highest after isolated curettage, indicating that (local) adjuvant treatment is desired to obtain immediate local control. Complications were common and impaired function.

Salvage of a Fractured Proximal Ulnar Osteoarticular Allograft Using a Medial Femoral Condyle Free Flap: A Case Report.

CASE: We present the case of a 47-year-old paraplegic woman who underwent resection of an intermediate-grade chondrosarcoma in the proximal ulna, which was initially reconstructed with an osteoarticular allograft. However, after more than 25 years without complications, she sustained an intra-articular fracture of the allograft, which was then successfully treated using a vascularized medial femoral condyle (MFC) flap and anterolateral thigh flap. The patient has subsequently recovered her baseline elbow function, has no pain, and can use her wheelchair without restrictions. CONCLUSION: Free MFC flaps are viable options to salvage osteoarticular allografts that are affected by intra-articular fractures.

Aneurysmal bone cyst: the role of cryosurgery as local adjuvant treatment.

BACKGROUND: Aneurysmal bone cysts (ABCs) are most often treated with intralesional surgery (curettage) and additional bone grafting. There is debate on whether or not to use adjuvant therapy to decrease the local recurrence rate. This study is done to assess the outcome of curettage and cryosurgery as a treatment of ABC. METHODS: We analyzed 80 consecutive cases of ABC treated with curettage and cryosurgery. Patients were followed minimal 24 months after surgery (average 55 months, range 24-122 months) with physical examination and radiographs. Functional outcome was evaluated using the musculoskeletal tumor society score (MSTS). RESULTS: The 80 patients were all treated with curettage and cryosurgery. Additional bone grafting was used in 73 patients, osteosynthesis in 12 and spondylodesis in 1 patient. Four local recurrences were found in this study, a recurrence rate of 5%. All local recurrences were treated successfully with curettage and cryosurgery again 7-33 months after the initial surgery. Postoperative one fracture, one wound infection, and three transient nerve palsy occurred. The average MSTS score was 29.2 at follow-up. CONCLUSIONS: The use of cryosurgery as adjuvant therapy results in a lower local recurrence rate when compared to other publications for the treatment of ABC and excellent functional results.

Survival of massive allografts in segmental oncological bone defect reconstructions.

Reconstructions of large segmental bone defects after resection of bone tumours with massive structural allografts have a high number of reported complications including fracture, infection and non-union. Our goal is to report the survival and complications of massive allografts in our patients. A total of 32 patients were evaluated for fracture, infection, non-union rate and survival of their massive allograft reconstructions. The average follow-up for this group was five years and three months. The total fracture rate was 13% with a total infection rate of 16%. We found a low union rate of 25%. The total survival of the allografts was 80.8% (+/- 18.7%) after five years. We found a five-year allograft survival of 80.8% which is comparable with other studies.

The effect of surgery in tenosynovial giant cell tumours as measured by patient-reported outcomes on quality of life and joint function.

AIMS: The aim of this study was to evaluate health-related quality of life (HRQoL) and joint function in tenosynovial giant cell tumour (TGCT) patients before and after surgical treatment. PATIENTS AND METHODS: This prospective cohort study run in two Dutch referral centres assessed patient-reported outcome measures (PROMs; 36-Item Short-Form Health Survey (SF-36), visual analogue scale (VAS) for pain, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)) in 359 consecutive patients with localized- and diffuse-type TGCT of large joints. Patients with recurrent disease (n = 121) and a wait-and-see policy (n = 32) were excluded. Collected data were analyzed at specified time intervals preoperatively (baseline) and/or postoperatively up to five years. RESULTS: A total of 206 TGCT patients, 108 localized- and 98 diffuse-type, were analyzed. Median age at diagnosis of localized- and diffuse-type was 41 years (interquartile range (IQR) 29 to 49) and 37 years (IQR 27 to 47), respectively. SF-36 analyses showed statistically significant and clinically relevant deteriorated preoperative and immediate postoperative scores compared with general Dutch population means, depending on subscale and TGCT subtype. After three to six months of follow-up, these scores improved to general population means and continued to be fairly stable over the following years. VAS scores, for both subtypes, showed no statistically significant or clinically relevant differences pre- or postoperatively. In diffuse-type patients, the improvement in median WOMAC score was statistically significant and clinically relevant preoperatively versus six to 24 months postoperatively, and remained up to five years' follow-up. CONCLUSION: Patients with TGCT report a better HRQoL and joint function after surgery. Pain scores, which vary hugely between patients and in patients over time, did not improve. A disease-specific PROM would help to decipher the impact of TGCT on patients' daily life and functioning in more detail. Cite this article: Bone Joint J 2019;101-B:272-280.

Oncological and functional results of cryosurgical therapy of enchondromas and chondrosarcomas grade 1.

BACKGROUND AND OBJECTIVES: Cryosurgery using liquid nitrogen is used as adjuvant treatment after intralesional resection of bone tumours to induce cell death. It is applied to enlarge the oncological margins of resection and to reduce the local recurrence rate. The objective of this study is to analyze the oncological and functional results. METHODS: We studied the oncological and functional results of curettage and cryosurgery in 123 patients with 130 tumors. There were 75 enchondromas and 55 chondrosarcomas grade 1. The minimal follow-up period for all patients was 2 years (range 24-119 months). RESULTS: During follow-up one local recurrence of an active enchondroma and one local recurrence of an aggressive enchondroma occurred. They were treated with curettage and cryosurgery again. Both patients were disease-free at minimum of 3 years follow-up. No local recurrences after treatment of chondrosarcoma grade 1 were seen. Functional scores, according to the MSTS scoring system, showed an average score of 28 points (94%) at 2 years follow-up. Post-operative fractures were seen in 18 patients (14%). CONCLUSIONS: Curettage and cryosurgery for enchondroma and chondrosarcoma grade 1 has excellent oncological and functional results. The post-operative management has been adjusted to reduce the number of fractures.

Treatments of tenosynovial giant cell tumours of the temperomandibular joint: a report of three cases and a review of literature.

Tenosynovial giant cell tumours (TGCTs) are benign lesions affecting synovial joints. The classified subtypes are localized and diffuse. They seldom occur in the temporomandibular joint (TMJ). The aim of this study is to report on three new cases and to review the literature. One patient had surgical debulking with adjuvant external beam radiation therapy (EBRT). After 1year of follow-up, no evidence of disease was presented. The second patient was misdiagnosed and treated with denosumab. Debulking with adjuvant EBRT followed. Ten months postoperatively, no disease progression was seen. The third patient received systemic nilotinib and remained stable for over 5years. The literature review included 106 cases of which 95 had diffuse subtype. Most patients, had surgical excision. Thirteen (14%) patients received adjuvant EBRT. Eleven (14%) recurrences were identified. After 1-, 5- and 10 years of follow-up, an overall progression-free survival (PFS) of 99% (95% confidence interval (CI) 0.96-1), 80% (95% CI 0.68-0.94), 67% (95% CI 0.51-0.90) was calculated, respectively. Treatments for diffuse-TGCT-TMJ should be individualized depending on age, severity of symptoms, extent of disease and progression, expected mutilation of surgical interference, and current systemic treatment options. In stable disease a 'wait and see' policy, is a viable option. Additional treatments should be reserved for symptomatic, irresectable tumours or residual disease after surgical treatment with persistent complaints.

Severity classification of Tenosynovial Giant Cell Tumours on MR imaging.

AIM: Current development of novel systemic agents requires identification and monitoring of extensive Tenosynovial Giant Cell Tumours (TGCT). This study defines TGCT extension on MR imaging to classify severity. METHODS: In part one, six MR parameters were defined by field-experts to assess disease extension on MR images: type of TGCT, articular involvement, cartilage-covered bone invasion, and involvement of muscular/tendinous tissue, ligaments or neurovascular structures. Inter- and intra-rater agreement were calculated using 118 TGCT MR scans. In part two, the previously defined MR parameters were evaluated in 174 consecutive, not previously used, MR-scans. TGCT severity classification was established based on highest to lowest Hazard Ratios (HR) on first recurrence. RESULTS: In part one, all MR parameters showed good inter- and intra-rater agreement (Kappa≥0.66). In part two, cartilage-covered bone invasion and neurovascular involvement were rarely appreciated (<13%) and therefore excluded for additional analyses. Univariate analyses for recurrent disease yielded positive associations for type of TGCT HR12.84(95%CI4.60-35.81), articular involvement HR6.00(95%CI2.14-16.80), muscular/tendinous tissue involvement HR3.50(95%CI1.75-7.01) and ligament-involvement HR4.59(95%CI2.23-9.46). With these, a TGCT severity classification was constructed with four distinct severity-stages. Recurrence free survival at 4 years (log rank p < 0.0001) was 94% in mild localized (n56, 1 recurrence), 88% in severe localized (n31, 3 recurrences), 59% in moderate diffuse (n32, 12 recurrences) and 36% in severe diffuse (n55, 33 recurrences). CONCLUSION: The proposed TGCT severity classification informs physicians and patients on disease extent and risk for recurrence after surgical treatment. Definition of the most severe subgroup attributes to a universal identification of eligible patients for systemic therapy or trials for novel agents.

Cryosurgery as Additional Treatment in Tenosynovial Giant Cell Tumors.

Introduction. Tenosynovial giant cell tumors (TGCT) emerge from the synovium and can behave aggressively. Surgical resection is the standard treatment. However, up to half of the patients with diffuse type show recurrences. Several additional treatments have been applied to reduce recurrences; none of these treatments was proven to be superior to surgical resection solely. This article describes the results of additional cryosurgery to surgical resection. Materials and Methods. We retrospectively evaluated 141 TGCT patients, between 1999 and 2007. Twelve patients had additional cryosurgery. The knee (n = 8), hip (n = 2), ankle (n = 1), and elbow (n = 1) were affected. Primary outcome variables were treatment indications, recurrences, and complications. Results. Indications for additional cryosurgery were extended disease, bone involvement, and locations that are difficult to surgically get disease-free such as cruciate ligaments. Five patients had recurrent disease, all of which had prior treatments. None of the primary treated patients had recurrent disease. One patient had a deep infection. Discussion. Cryosurgery may serve as an additional treatment for diffuse TCGT in selected cases. However, because of the small number of patients and the heterogeneous group we could not prove an advantage of additional cryosurgery over surgical resection only. Cryosurgery should be considered for further evaluation in a prospective study. If there is any effect it would be helpful, especially in patients with multiple TGCT recurrences.

Altered phase-transitions in tibialis anterior and medial gastrocnemius during walking after limbsaving surgery.

OBJECTIVE: In normal gait onset activity in tibialis anterior at end stance is closely linked to reduction in activity in medial gastrocnemius. Is a similar transition also present in patients undergoing limb-saving surgery? METHODS: Nineteen subjects after limb-saving surgery of the lower extremity and ten age-matched controls were compared. Patients walked on a treadmill at their preferred speed. Bipolar surface EMG activity was recorded from the tibialis anterior and the medial gastrocnemius. RESULTS: Patients showed asymmetry in gait. In controls a close tibialis anterior and medial gastrocnemius connection was seen. The close link between ipsilateral tibialis anterior and medial gastrocnemius was absent in patients. Instead, a link was found between tibialis anterior onset in the affected and medial gastrocnemius onset in the non-affected leg. CONCLUSIONS: This finding suggests that two control mechanisms can be seen: a contralateral connection between tibialis and gastrocnemius and a less important ipsilateral connection. This means that automated phase switching in patients does not rely primarily on ipsilateral mechanisms but that instead the onset of the ipsilateral swing is linked to the moment of load acceptance by the contralateral leg These results are strikingly similar to those obtained in simulated limping by normal subjects. SIGNIFICANCE: Patients after limbsaving surgery have a clinically significant problem that creates aberrant gait patterns. This study provides new information about linking of ankle dorsiflexors and plantarflexors, as well as reporting the uncoupling of this mechanism in these patients after major surgery.

Hemicortical resection and inlay allograft reconstruction for primary bone tumors: a retrospective evaluation in the Netherlands and review of the literature.

BACKGROUND: Selected primary tumors of the long bones can be adequately treated with hemicortical resection, allowing for optimal function without compromising the oncological outcome. Allografts can be used to reconstruct the defect. As there is a lack of studies of larger populations with sufficient follow-up, little is known about the outcomes of these procedures. METHODS: In this nationwide retrospective study, all patients treated with hemicortical resection and allograft reconstruction for a primary bone tumor from 1989 to 2012 were evaluated for (1) mechanical complications and infection, (2) oncological outcome, and (3) failure or allograft survival. The minimum duration of follow-up was twenty-four months. RESULTS: The study included 111 patients with a median age of twenty-eight years (range, seven to seventy-three years). The predominant diagnoses were adamantinoma (n = 37; 33%) and parosteal osteosarcoma (n = 18; 16%). At the time of review, 104 patients (94%) were alive (median duration of follow-up, 6.7 years). Seven patients (6%) died, after a median of twenty-six months. Thirty-seven patients (33%) had non-oncological complications, with host bone fracture being the most common (n = 20, 18%); all healed uneventfully. Other complications included nonunion (n = 8; 7%), infection (n = 8; 7%), and allograft fracture (n = 3; 3%). Of ninety-seven patients with a malignant tumor, fifteen (15%) had residual or recurrent tumor and six (6%) had metastasis. The risk of complications and fractures increased with the extent of cortical resection. CONCLUSIONS: Survival of hemicortical allografts is excellent. Host bone fracture is the predominant complication; however, none of these fractures necessitated allograft removal in our series. The extent of resection is the most important risk factor for complications. Hemicortical resection is not recommended for high-grade lesions; however, it may be superior to segmental resection for treatment of carefully selected tumors, provided that it is possible to obtain adequate margins. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Intercalary allograft reconstructions following resection of primary bone tumors: a nationwide multicenter study.

BACKGROUND: Favorable reports on the use of massive allografts to reconstruct intercalary defects underline their place in limb-salvage surgery. However, little is known about optimal indications as reports on failure and complication rates in larger populations remain scarce. We evaluated the incidence of and risk factors for failure and complications, time to full weight-bearing, and optimal fixation methods for intercalary allografts after tumor resection. METHODS: A retrospective study was performed in all four centers of orthopaedic oncology in the Netherlands. All consecutive patients reconstructed with intercalary (whole-circumference) allografts after tumor resection in the long bones during 1989 to 2009 were evaluated. The minimum follow-up was twenty-four months. Eighty-seven patients with a median age of seventeen years (range, 1.5 to 77.5 years) matched inclusion criteria. The most common diagnoses were osteosarcoma, Ewing sarcoma, adamantinoma, and chondrosarcoma. The median follow-up period was eighty-four months (range, twenty-five to 262 months). Ninety percent of tumors were localized in the femur or the tibia. RESULTS: Fifteen percent of our patients experienced a graft-related failure. The major complications were nonunion (40%), fracture (29%), and infection (14%). Complications occurred in 76% of patients and reoperations were necessary in 70% of patients. The median time to the latest complication was thirty-two months (range, zero to 200 months). The median time to full weight-bearing was nine months (range, one to eighty months). Fifteen grafts failed, twelve of which failed in the first four years. None of the thirty-four tibial reconstructions failed. Reconstruction site, patient age, allograft length, nail-only fixation, and non-bridging osteosynthesis were the most important risk factors for complications. Adjuvant chemotherapy and irradiation had no effects on complication rates. CONCLUSIONS: We report high complication rates and considerable failure rates for the use of intercalary allografts; complications primarily occurred in the first years after surgery, but some occurred much later after surgery. To reduce the number of failures, we recommend reconsidering the use of allografts for reconstructions of defects that are ≥15 cm, especially in older patients, and applying bridging osteosynthesis with use of plate fixation.

High prevalence of late adverse events in malignant bone tumour survivors diagnosed at adult age.

BACKGROUND: Late treatment-related adverse events are particularly prevalent in survivors of childhood bone cancer because of the combination of cytotoxic drugs, major surgery and radiotherapy. Existing studies for late toxicity in survivors of Ewing's sarcoma (ES) and osteosarcoma (OS) diagnosed at adult age have focused on specific sequelae. We investigated a broad spectrum of potential late effects in these patients. METHODS: Relapse-free OS and ES patients aged ≥ 16 at diagnosis and treated at the Radboud University Medical Centre (1982-2007) were invited for systematic late toxicity screening. This included history taking, physical examination, echocardiogram, bone densitometry, audiogram, and serum and urine screening for renal toxicity and infertility. Adverse events were graded according to the Common Terminology Criteria for Adverse Events version 3.0. RESULTS: In 24 survivors (63% male, mean age at screening 45.7 years, mean follow-up 10.9 years, 70% OS) we found a median of eight adverse events. Frequent findings included abnormal gait, osteoporosis, pain, left ventricular systolic dysfunction, obesity and nephropathy. The maximum grade of any adverse event was mild in four (17%), moderate in 11 (46%), severe in six (25%), and disabling in three cases (13%). There was a trend towards more events in patients diagnosed at an older age. CONCLUSION: The incidence of late adverse events in this study of survivors of bone tumours diagnosed at adult age is higher than in any previously published childhood cancer survivorship study. Older patients seem to be particularly at risk. Our findings underscore the need for systematic screening of late effects in bone cancer survivors of adult age at diagnosis.

Prognostic and therapeutic relevance of the IGF pathway in Ewing's sarcoma patients.

The optimal target and timing of drugs interfering with the insulin-like growth factor (IGF) signaling system in Ewing's sarcoma (ES) remain undetermined. We examined the expression of IGF signaling proteins in ES samples taken before and after chemotherapy, and speculate about the optimal way of treating ES patients in the future. Tumor material (36 initial biopsies and 24 resection specimens after neoadjuvant chemotherapy) and follow-up data of 41 patients treated for ES at the Radboud University Nijmegen Medical Centre were analyzed. Immunohistochemical staining was done for IGF1, IGF2, IGFBP3, IGF-1R, phosphorylated AKT (pAKT), phosphorylated mTOR (pmTOR), and phosphorylated ERK (pERK), and staining intensity was scored semiquantitatively. Change of protein expression during treatment, correlations of effector cascade signaling, and influence on progression-free (PFS) and overall survival (OS) were tested. All potential targets were widely expressed at both time points. After chemotherapy, pmTOR expression decreased significantly (p = 0.021) while IGFBP3 increased (p = 0.005). Correlations exist between IGF-1R and pERK (ρ = 0.286, p = 0.031), IGF-1R and pAKT (ρ = 0.269, p = 0.045), pAKT and pERK (ρ = 0.460, p = 0.000), and pERK and pmTOR (ρ = 0.273, p = 0.038). In therapy-naive samples, combined expression of pAKT, pmTOR, and pERK predicted worse PFS (median, 11 vs. 32 months; p = 0.039) and OS (median, 18 vs. 83 months; p = 0.023). We identify an unfavorable prognostic group of ES patients with widely activated IGF-effector cascades, demonstrate cooperation between the different downstream pathways, and show how expression of IGF-related proteins may change after exposure to chemotherapy. These findings should be taken into account when designing future trials with IGF-targeting agents. We suggest the prospective exploration of chemotherapy and multi-target tyrosine kinase inhibitors in the first-line setting.

Targeted therapy for Ewing's sarcoma: significance of heterogeneity.

BACKGROUND: Survival in Ewing's sarcoma (ES) is limited. Experience with insulin-like growth factor targeting drugs, which require specific molecular tumour alterations, herald a major breakthrough. We screened for tumour heterogeneity within patients by DNA quantification. MATERIALS AND METHODS: DNA image cytometry (IC) was performed on 41 samples from 21 patients, evaluating if ploidy state remained constant over time and between different lesions within patients and the prognostic value of ploidy was assessed. RESULTS: DNA content varied over time and different ploidy states were found to coexist at a single timepoint. Non-diploid DNA content was associated with shorter overall survival (median, 19 vs. 84 months, p=0.047). CONCLUSION: We encountered a change and heterogeneity of ploidy state. This implies that screening for targets on a single tumour sample is insufficient and may lead to under- or overtreatment. The fact that non-diploid DNA content was associated with an adverse outcome confirms that this technique discriminates biologically different tumour clones.

Bone grafting of cryosurgically treated bone defects: experiments in goats.

It is hypothesized that cryosurgically treated bone defects are inappropriate host sites for cancellous bone grafting. The influence of autologous cancellous bone grafting on the healing of cryosurgically treated gap defects of long bones was investigated. A unilateral in vivo experiment was done to study bone strength and graft incorporation in the goat. The lining of a cylindrical defect of the femoral diaphysis was treated with a closed liquid nitrogen cryoprobe in 62 goats. Thirty-one animals received an impacted, morselized, cancellous bone graft harvested from the sternum. The other 31 animals served as controls. At 0, 4, 7, 10, 13, 16, and 26 weeks animals were euthanized and the femurs were evaluated for torsional strength, computed tomography, and histologic assessment. Specimens with a bone graft showed no significant increase in torsional strength with time compared to the controls. In all goats euthanized at 10 weeks or later, the graft was resorbed. The amount of bone apposition at the site of the cryosurgical lesion and the time at which the defect was bridged were similar in both groups. Autologous cancellous bone grafting does not accelerate healing of cryosurgically treated, stable, diaphyseal defects in the goat.