IntroductionHigh-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment ...options, emphasising the need for novel therapies. Mutations in the genes IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II–IV glioma and 20% of intrahepatic cholangiocarcinoma. IDH1/2-mutated cancer cells produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine.Methods and analysisWe describe a dose-finding phase Ib/II clinical trial, in which patients with IDH1/2-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine. Dose escalation is performed according to a 3+3 dose-escalation scheme. The primary objective is to determine the maximum tolerated dose to establish the recommended dose for a phase II clinical trial. Secondary objectives of the study include (1) determination of pharmacokinetics and toxic effects of the study therapy, for which metformin and chloroquine serum levels will be determined over time; (2) investigation of tumour responses to metformin plus chloroquine in IDH1/2-mutated cancers using CT/MRI scans; and (3) whether tumour responses can be measured by non-invasive D-2HG measurements (mass spectrometry and magnetic resonance spectroscopy) of tumour tissue, serum, urine, and/or bile or next-generation sequencing of circulating tumour DNA (liquid biopsies). This study may open a novel treatment avenue for IDH1/2-mutated high-grade chondrosarcoma, glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications.Ethics and disseminationThis study has been approved by the medical-ethical review committee of the Academic Medical Center, Amsterdam, The Netherlands. The report will be submitted to a peer-reviewed journal.Trial registration numberThis article was registered at ClinicalTrials.gov identifier (NCT02496741): Pre-results.
Abstract We aimed to evaluate the prognostic significance of traditional clinical predictors in osteosarcoma through an international collaboration of 10 teams of investigators (2680 patients) who ...participated. In multivariate models the mortality risk increased with older age, presence of metastatic disease at diagnosis, development of local recurrence when the patient was first seen, use of amputation instead of limb salvage/wide resection, employment of unusual treatments, use of chemotherapeutic regimens other than anthracycline and platinum and use of methotrexate. It was also influenced by the site of the tumour. The risk of metastasis increased when metastatic disease was present at the time the patient was first seen and also increased with use of amputation or unusual treatment combinations or chemotherapy regimens not including anthracycline and platinum. Local recurrence risk was higher in older patients, in those who had local recurrence when first seen and when no anthracycline and platinum were used in chemotherapy. Results were similar when limited to patients seen after 1990 and treated with surgery plus combination chemotherapy. This large-scale international collaboration identifies strong predictors of major clinical outcomes in osteosarcoma.
Introduction. Chondrosarcomas are malignant bone tumors that are characterized by the production of chondroid tissue. Since radiation therapy and chemotherapy have limited effect on chondrosarcoma, ...treatment of most patients depends on surgical resection. We conducted this study to identify independent predictive factors and survival characteristics for conventional central chondrosarcoma and dedifferentiated central chondrosarcoma. Methods. A systematic literature review was performed in September 2014 using the Pubmed, Embase, and Cochrane databases. Subsequent to a beforehand-composed selection procedure we included 13 studies, comprising a total of 1114 patients. Results. The prognosis of central chondrosarcoma is generally good for the histologically low-grade tumors. Prognosis for the high-grade chondrosarcoma and the dedifferentiated chondrosarcoma is poor with lower survival rates. Poor prognostic factors in conventional chondrosarcoma for overall survival are high-grade tumors and axial/pelvic tumor location. In dedifferentiated chondrosarcoma the percentage of dedifferentiated component has significant influence on disease-free survival. Conclusion. Despite the fact that there are multiple prognostic factors identified, as shown in this study, there is a need for prospective and comparative studies. The resulting knowledge about prognostic factors and survival can give direction in the development of better therapies. This could eventually lead to an evidence-based foundation for treating chondrosarcoma patients.
Background and Objectives
In a previous conducted study functional outcome of young patients with bone sarcoma located around the knee was longitudinally evaluated during the first 2 years ...postoperatively. Functional outcome improved significantly over the first 2 years. The purpose of this descriptive study was to evaluate the functional outcome of these patients at long‐term follow‐up of 7 years.
Methods
Functional outcome was assessed with the TESS, MSTS, Baecke questionnaire, and three functional performance tests: time up and down stairs (TUDS), various walking activities (VWA), and the 6‐min walking test (6MWT). Linear Mixed Model has been employed for the repeated measurements.
Results
Twenty patients of the original study (n = 44) participated in the current study. Fifteen limb‐salvage and five ablative surgery patients, median follow‐up 7.4 years (6.8‐8.0) (CI 95%), mean age 22.3 years (18.2‐31.6). Between 2 and 7 years after surgery, 8 limb‐salvage patients (53%) encountered surgery related complications. Questionnaires and functional performance tests showed no significant difference in functional outcome between 2 years and 7 years after surgery (P < 0.05).
Conclusions
Between 2 years and follow‐up at average 7 years after surgery no further improvements were noticed at young patients with a bone sarcoma located around the knee.
Background
Patient reported outcome data in bone metastatic disease are scarce and it would be useful to have normative data and understand what patients are at risk for poor function and more pain.
...Objectives
We aimed to assess what factors are independently associated with physical function and pain intensity in patients with bone metastasis.
Methods
We included data from 211 patients with bone metastasis who completed a survey (2014‐2016) including the PROMIS Physical Function Cancer and PROMIS Pain Intensity questionnaires.
Results
Prostate (P < .001) and thyroid carcinoma (P = .007) were associated with better function and having other disabling conditions (P = 0.035) was associated with worse function. Prostate carcinoma (P = .001) and lymphoma (P = .007) were associated with less pain. There was a moderate correlation between pain and function (P < .001). Function was substantially worse as compared to a US reference population of patients with cancer (P < .001), whereas pain was slightly less compared to the US general population average (P < .001).
Conclusions
Patients with bone metastasis have a poor physical function. Physical function and pain intensity depend on tumor histology, but also on potentially modifiable factors such as other disabling conditions.
Level of Evidence
Level III, prognostic study.
Modular endoprostheses are commonly used to reconstruct defects of the distal femur and proximal tibia after bone tumor resection. Because limb salvage surgery for bone sarcomas is relatively new, ...becoming more frequently used since the 1980s, studies focusing on the long-term results of such prostheses in treatment of primary tumors are scarce. (1) What proportion of patients experience a mechanical complication with the MUTARS super( registered ) modular endoprosthesis when used for tumor reconstruction around the knee, and what factors may be associated with mechanical failure? (2) What are the nonmechanical complications? (3) What are the implant failure rates at 5, 10, and 15 years? (4) How often is limb salvage achieved using this prosthesis? Between 1995 and 2010, endoprostheses were the preferred method of reconstruction after resection of the knee in adolescents and adults in our centers. During that period, we performed 114 MUTARS super( registered ) knee replacements in 105 patients; no other endoprosthetic systems were used. Four patients (four of 105 4%) were lost to followup, leaving 110 reconstructions in 101 patients for review. The reverse Kaplan-Meier method was used to calculate median followup, which was equal to 8.9 years (95% confidence interval CI, 8.0-9.7). Mean age at surgery was 36 years (range, 13-82 years). Predominant diagnoses were osteosarcoma (n = 56 55%), leiomyosarcoma of bone (n = 10 10%), and chondrosarcoma (n = 9 9%). In the early period of our study, we routinely used uncemented uncoated implants for primary reconstructions. Later, hydroxyapatite (HA)-coated implants were the standard. Eighty-nine reconstructions (89 of 110 81%) were distal femoral replacements (78 uncemented 78 of 89 {88%}, 42 of which were HA-coated 42 of 78 {54%}) and 21 (21 of 110 19%) were proximal tibial replacements. In 26 reconstructions (26 of 110 24%), the reconstruction was performed for a failed previous reconstruction. We used a competing risk model to estimate the cumulative incidence of implant failure. Complications of soft tissue or instability occurred in seven reconstructions (seven of 110 6%). With the numbers we had, for uncemented distal femoral replacements, we could not detect a difference in loosening between revision (five of 17 29%) and primary reconstructions (eight of 61 13%) (hazard ratio HR, 1.72; 95% CI, 0.55-5.38; p = 0.354). Hydroxyapatite-coated uncemented implants had a lower risk of loosening (two of 42 5%) than uncoated uncemented implants (11 of 36 31%) (HR, 0.23; 95% CI, 0.05-1.06; p = 0.060). Structural complications occurred in 15 reconstructions (15 of 110 14%). Infections occurred in 14 reconstructions (14 of 110 13%). Ten patients had a local recurrence (10 of 101 10%). With failure for mechanical reasons as the endpoint, the cumulative incidences of implant failure at 5, 10, and 15 years were 16.9% (95% CI, 9.6-24.2), 20.7% (95% CI, 12.5-28.8%), and 37.9% (95% CI, 16.1-59.7), respectively. We were able to salvage some of the failures so that at followup, 90 patients (90 of 101 89%) had a MUTARS super( registered ) in situ. Although no system has yet proved ideal to restore normal function and demonstrate long-term retention of the implant, MUTARS super( registered ) modular endoprostheses represent a reliable long-term option for knee replacement after tumor resection, which seems to be comparable to other modular implants available to surgeons. Although the number of patients is relatively small, we could demonstrate that with this prosthesis, an uncemented HA-coated implant is useful in achieving durable fixation. Level IV, therapeutic study.
Reconstruction of periacetabular defects after pelvic tumor resection ranks among the most challenging procedures in orthopaedic oncology, and reconstructive techniques are generally associated with ...dissatisfying mechanical and nonmechanical complication rates. In an attempt to reduce the risk of dislocation, aseptic loosening, and infection, we introduced the LUMiC super( registered ) prosthesis (implantcast, Buxtehude, Germany) in 2008. The LUMiC super( registered ) prosthesis is a modular device, built of a separate stem (hydroxyapatite-coated uncemented or cemented) and acetabular cup. The stem and cup are available in different sizes (the latter of which is also available with silver coating for infection prevention) and are equipped with sawteeth at the junction to allow for rotational adjustment of cup position after implantation of the stem. Whether this implant indeed is durable at short-term followup has not been evaluated. (1) What proportion of patients experience mechanical complications and what are the associated risk factors of periacetabular reconstruction with the LUMiC super( registered ) after pelvic tumor resection? (2) What proportion of patients experience nonmechanical complications and what are the associated risk factors of periacetabular reconstruction with the LUMiC super( registered ) after pelvic tumor resection? (3) What is the cumulative incidence of implant failure at 2 and 5 years and what are the mechanisms of reconstruction failure? (4) What is the functional outcome as assessed by Musculoskeletal Tumor Society (MSTS) score at final followup? We performed a retrospective chart review of every patient in whom a LUMiC super( registered ) prosthesis was used to reconstruct a periacetabular defect after internal hemipelvectomy for a pelvic tumor from July 2008 to June 2014 in eight centers of orthopaedic oncology with a minimum followup of 24 months. Forty-seven patients (26 men 55%) with a mean age of 50 years (range, 12-78 years) were included. At review, 32 patients (68%) were alive. The reverse Kaplan-Meier method was used to calculate median followup, which was equal to 3.9 years (95% confidence interval CI, 3.4-4.3). During the period under study, our general indications for using this implant were reconstruction of periacetabular defects after pelvic tumor resections in which the medial ilium adjacent to the sacroiliac joint was preserved; alternative treatments included hip transposition and saddle or custom-made prostheses in some of the contributing centers; these were generally used when the medial ilium was involved in the tumorous process or if the LUMiC super( registered ) was not yet available in the specific country at that time. Conventional chondrosarcoma was the predominant diagnosis (n = 22 47%); five patients (11%) had osseous metastases of a distant carcinoma and three (6%) had multiple myeloma. Uncemented fixation (n = 43 91%) was preferred. Dual-mobility cups (n = 24 51%) were mainly used in case of a higher presumed risk of dislocation in the early period of our study; later, dual-mobility cups became the standard for the majority of the reconstructions. Silver-coated acetabular cups were used in 29 reconstructions (62%); because only the largest cup size was available with silver coating, its use depended on the cup size that was chosen. We used a competing risk model to estimate the cumulative incidence of implant failure. Six patients (13%) had a single dislocation; four (9%) had recurrent dislocations. The risk of dislocation was lower in reconstructions with a dual-mobility cup (one of 24 4%) than in those without (nine of 23 39%) (hazard ratio, 0.11; 95% CI, 0.01-0.89; p = 0.038). Three patients (6%; one with a preceding structural allograft reconstruction, one with poor initial fixation as a result of an intraoperative fracture, and one with a cemented stem) had loosening and underwent revision. Infections occurred in 13 reconstructions (28%). Median duration of surgery was 6.5 hours (range, 4.0-13.6 hours) for patients with an infection and 5.3 hours (range, 2.8-9.9 hours) for those without (p = 0.060); blood loss was 2.3 L (range, 0.8-8.2 L) for patients with an infection and 1.5 L (range, 0.4-3.8 L) for those without (p = 0.039). The cumulative incidences of implant failure at 2 and 5 years were 2.1% (95% CI, 0-6.3) and 17.3% (95% CI, 0.7-33.9) for mechanical reasons and 6.4% (95% CI, 0-13.4) and 9.2% (95% CI, 0.5-17.9) for infection, respectively. Reasons for reconstruction failure were instability (n = 1 2%), loosening (n = 3 6%), and infection (n = 4 9%). Mean MSTS functional outcome score at followup was 70% (range, 33%-93%). At short-term followup, the LUMiC super( registered ) prosthesis demonstrated a low frequency of mechanical complications and failure when used to reconstruct the acetabulum in patients who underwent major pelvic tumor resections, and we believe this is a useful reconstruction for periacetabular resections for tumor or failed prior reconstructions. Still, infection and dislocation are relatively common after these complex reconstructions. Dual-mobility articulation in our experience is associated with a lower risk of dislocation. Future, larger studies will need to further control for factors such as dual-mobility articulation and silver coating. We will continue to follow our patients over the longer term to ascertain the role of this implant in this setting. Level IV, therapeutic study.
Histological response to chemotherapy is an important prognostic factor in osteosarcoma, influencing therapeutic considerations. It would be advantageous to be able to assess chemotherapy response, ...and predict survival, prior to tumour resection. Colour Doppler US (CDUS) is non-invasive, non-demanding for the patient, and easy to plan. This makes the method especially suitable for children, who comprise the majority of patients.
To establish the value of CDUS for pre-operative prediction of chemotherapy response and survival, using widely available US equipment.
CDUS was performed in 21 consecutive patients before and after chemotherapy. Peak systolic velocity (PSV) in the soft-tissue component of the tumour and quotient of resistive index (QRI) of the feeding artery and contralateral control were calculated. A pathologist, unaware of CDUS results, assessed the response to chemotherapy after resection.
QRI change after chemotherapy was significantly higher in histological responders. No correlation of QRI change with survival was found. There was no significant difference in PSV change comparing any subgroup. CDUS appeared useful in predicting chemotherapy response (sensitivity 83%, specificity 86%), especially for negative response (predictive value 92%). Survival could not be predicted accurately.
CDUS can predict chemotherapy response, but not survival. The method could be useful in planning treatment prior to definitive surgery.
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