Clear cell chondrosarcoma: a review of clinicopathologic characteristics, differential diagnoses, and patient management.

Clear cell chondrosarcoma (CCC), an extremely rare primary bone tumor, is currently classified by the World Health Organization as a low-grade malignant cartilaginous neoplasm. Clinically, CCC occurs primarily in males with a peak incidence in the third to fifth decades of life, and occasionally, it presents in skeletally immature patients. Unlike conventional chondrosarcoma, CCC has a predilection for the epiphysis of long bones and often displays radiologic features reminiscent of chondroblastoma. The recommended treatment is wide operative resection. CCC has a local recurrence rate of approximately 30%, and nearly 20% cases metastasize mainly to bone and lung often a decade after surgical intervention. Incomplete excision or curettage is associated with a high rate of recurrence. Histologically, the process is characterized by infiltrative lobules and sheets of round to oval cells with abundant cleared cytoplasm and well-defined cell borders associated with trabecula of osteoid and woven bone, scattered osteoclasts, and foci of conventional low-grade chondrosarcoma in about one-half of cases. Correlation with clinical and radiologic characteristics, such as epiphyseal location and young patient age, assists in establishing a correct diagnosis. Pathologic diagnosis of CCC is complicated by the low diagnostic accuracy of core needle biopsy, overlapping histologic features with other matrix-rich primary bone tumors, and a lack of a specific immunohistochemical and molecular profile. DNA methylation-based profiling classifier (sarcoma classifier) is one recent technologic advancement that may help to confirm the histopathological diagnosis of CCC or indicate the need for thorough reassessment in cases where results contradict previous conventional findings.

Preclinical Characterization and Phase I Trial Results of INBRX-109, A Third-Generation, Recombinant, Humanized, Death Receptor 5 Agonist Antibody, in Chondrosarcoma.

PURPOSE: Patients with unresectable/metastatic chondrosarcoma have poor prognoses; conventional chondrosarcoma is associated with a median progression-free survival (PFS) of <4 months after first-line chemotherapy. No standard targeted therapies are available. We present the preclinical characterization of INBRX-109, a third-generation death receptor 5 (DR5) agonist, and clinical findings from a phase I trial of INBRX-109 in unresectable/metastatic chondrosarcoma (NCT03715933). PATIENTS AND METHODS: INBRX-109 was first characterized preclinically as a DR5 agonist, with binding specificity and hepatotoxicity evaluated in vitro and antitumor activity evaluated both in vitro and in vivo. INBRX-109 (3 mg/kg every 3 weeks) was then evaluated in a phase I study of solid tumors, which included a cohort with any subtype of chondrosarcoma and a cohort with IDH1/IDH2-mutant conventional chondrosarcoma. The primary endpoint was safety. Efficacy was an exploratory endpoint, with measures including objective response, disease control rate, and PFS. RESULTS: In preclinical studies, INBRX-109 led to antitumor activity in vitro and in patient-derived xenograft models, with minimal hepatotoxicity. In the phase I study, INBRX-109 was well tolerated and demonstrated antitumor activity in unresectable/metastatic chondrosarcoma. INBRX-109 led to a disease control rate of 87.1% [27/31; durable clinical benefit, 40.7% (11/27)], including two partial responses, and median PFS of 7.6 months. Most treatment-related adverse events, including liver-related events, were low grade (grade ≥3 events in chondrosarcoma cohorts, 5.7%). CONCLUSIONS: INBRX-109 demonstrated encouraging antitumor activity with a favorable safety profile in patients with unresectable/metastatic chondrosarcoma. A randomized, placebo-controlled, phase II trial (ChonDRAgon, NCT04950075) will further evaluate INBRX-109 in conventional chondrosarcoma.

Biology and Management of High-Grade Chondrosarcoma: An Update on Targets and Treatment Options.

This review provides an overview of histopathology, clinical presentation, molecular pathways, and potential new systemic treatments of high-grade chondrosarcomas (CS), including grade 2−3 conventional, dedifferentiated, and mesenchymal CS. The diagnosis of CS combines radiological and histological data in conjunction with patient clinical presentations. Conventional CS is the most frequent subtype of CS (85%) and represents about 25% of primary bone tumors in adults; they can be categorized according to their bone location into central, peripheral, and periosteal chondrosarcomas. Central and peripheral CS differ at the molecular level with either IDH1/2 mutations or EXT1/2 mutations, respectively. CDKN2A/B deletions are also frequent in conventional CS, as well as COL2A1 mutations. Dedifferentiated CS develops when low-grade conventional CS transforms into a high-grade sarcoma and most frequently exhibits features of osteosarcoma, fibrosarcoma, or undifferentiated pleomorphic sarcoma. Their molecular characteristics are similar to conventional CS. Mesenchymal CS is a totally different pathological entity exhibiting recurrent translocations. Their clinical presentation and management are different too. The standard treatment of CSs is wide en-bloc resection. CS are relatively radiotherapy resistant; therefore, doses >60 Gy are needed in an attempt to achieve local control in unresectable tumors. Chemotherapy is possibly effective in mesenchymal chondrosarcoma and is of uncertain value in dedifferentiated chondrosarcoma. Due to resistance to standard anticancer agents, the prognosis is poor in patients with metastatic or unresectable chondrosarcomas. Recently, the refined characterization of the molecular profile, as well as the development of new treatments, allow new therapeutic options for these rare tumors. The efficiency of IDH1 inhibitors in other malignancies suggests that these inhibitors will be part of IDH1/2 mutated conventional CS management soon. Other treatment approaches, such as PIK3-AKT-mTOR inhibitors, cell cycle inhibitors, and epigenetic or immune modulators based on improving our understanding of CS molecular biology, are emerging.

Non-Squamous Cell Malignancies of the Larynx.

OBJECTIVES/HYPOTHESIS: Non-squamous cell carcinoma (SCC) malignancies are rare, but well described laryngeal pathologies. However, the epidemiology and clinical behavior of these tumors is not well studied. STUDY DESIGN: Retrospective cohort study. METHODS: Patients diagnosed with non-squamous cell larynx cancer from 2004 to 2017 in the National Cancer Database were selected. Demographic, clinicopathologic factors, treatments, and survival were analyzed. Univariable and multivariable cox regression were performed. Survival was compared with a propensity score-matched (PSM) population of laryngeal SCC patients. RESULTS: A total of 136,235 cases of larynx cancer were identified. After excluding SCC variants, 2,172 (1.6%) patients met inclusion criteria. The most common histology was chondrosarcoma (374, 17.2%), followed by small cell (345, 15.9%), and spindle cell carcinoma (268, 12.3%). The most common treatment was surgery (683, 31.4%) followed by chemoradiation (409, 18.8%) and surgery and adjuvant radiation (288, 13.3%). Overall, 3- and 5-year survival was 67.9% and 59.4%, respectively. In multivariate analysis controlling for age, stage, comorbidity, histology, and treatment modality; chondrosarcoma had the best survival (hazard ratio [HR] 0.11, confidence interval [CI] 0.07-0.19, P < .001). In a PSM population, matched for age, stage, comorbidity, and treatments; non-SCC patients had significantly lower survival (51.5% vs. 59.9%, P < .001). CONCLUSION: A diverse range of non-squamous cell malignancies occur in the larynx. In general, these tumors have poor survival, with few exceptions such as chondrosarcoma. While the majority of these histologies undergo surgical-based treatments in other sites, only 53% of patients underwent surgical-based treatment in the larynx. These data could guide clinicians in determining the outcome of treatment in these patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:1771-1777, 2022.

Laryngeal Chondrosarcoma Characteristics and Survival Analysis in the National Cancer Database.

OBJECTIVE: To highlight various patient, tumor, diagnostic, and treatment characteristics of laryngeal chondrosarcoma (LC) as well as elucidate factors that may independently affect overall survival (OS) for LCs. STUDY DESIGN: Retrospective cohort study. SETTING: National Cancer Database (NCDB). METHODS: All LC cases from 2004 to 2016 were extracted from the NCDB. Several demographic, diagnostic, and treatment variables were compared between LC subgroups using χ2 and analysis of variance tests. Univariate and multivariate survival analyses were performed for LCs using univariate Kaplan-Meier analysis and Cox proportional hazards regression models. RESULTS: There were 348 LCs included in the main cohort. LCs were predominantly non-Hispanic white males with similar rates of private and government insurance (49.4% vs 45.4%). Most LCs (81.6%) underwent primary surgery, particularly partial and total laryngectomy. The 1-, 5-, and 10-year survivals for LC were 95.7%, 88.2%, and 66.3%, respectively. On multivariate analysis, lack of insurance (P = .019; hazard ratio [HR], 8.21; 95% CI, 1.40-48.03), high grade (P = .001; HR, 13.51; 95% CI, 3.08-59.26), and myxoid/dedifferentiated histological subtypes (P = .0111; HR, 10.74; 95% CI, 1.71-67.33) correlated with worse OS. No difference in OS was found between partial and total laryngectomy. CONCLUSION: This is the first multivariate survival analysis and largest single cohort study of LCs in the literature. Overall, LCs enjoy an excellent prognosis, with insurance status, grade, and histology as the main predictors of survival.

Dedifferentiated chondrosarcoma: current standards of care.

Dedifferentiated chondrosarcomas are aggressive variants of chondrosarcoma, associated with poor outcomes. Tumor biphasism is the norm. The majority of these tumors are symptomatic at presentation. Radiologically, large soft tissue masses with bony destruction predominate. Treatment protocols of these tumors are not well defined. Surgical resection forms the standard of care for localized disease. (Neo)adjuvant therapies remain controversial as the results from multiple (mainly retrospective) studies remain conflicting. Age at presentation, stage and ability to obtain negative resection margins are important prognostic factors. The overall prognosis is dismal. Newer and novel therapies targeting the complex genetic makeup of these tumors have renewed interest in the adjuvant setting that could hold promise in the near future.

Lay abstract Dedifferentiated chondrosarcomas are rare cancers composed of two components: a high-grade component and a low-grade component, with one abruptly blending into another. These rare tumors affect middle-aged individuals and present with pain and swelling in the affected site. X-rays and other scans often show tumor within the soft tissue with bony destruction. Although the precise treatment protocol is not well defined, surgery remains the standard of care for those where the tumor has not spread elsewhere. Once the disease spreads to other parts of the body, the outcome is very poor. The role of certain drugs targeting the tumor (chemotherapeutic agents) is controversial. This review briefly describes the genetic basis, treatment modalities involved and newer agents being developed for this lethal cancer.

Fresh Tissue Multi-omics Profiling Reveals Immune Classification and Suggests Immunotherapy Candidates for Conventional Chondrosarcoma.

PURPOSE: There is still no standard nonsurgical regimen for conventional chondrosarcoma (CHS). We aimed to identify whether any CHSs have a favored microenvironment for immunotherapy via multidimensional evaluation of the immunologic characteristics of this tumor. EXPERIMENTAL DESIGN: We obtained 98 newly-diagnosed CHS fresh tumors from several institutions and performed comprehensive analysis of data from CyTOF, whole-exome sequencing, and flow cytometry in 22 cases. Clinical data from immunotherapy responders and nonresponders were compared to explore possible biomarkers of immunotherapy response. Mechanism studies were conducted to interpret the biomarker phenotype. RESULTS: Based on the integrated data of single-cell CyTOF and flow cytometry, the CHS immune-microenvironment phenotypes were classified into three groups: subtype I, the "granulocytic-myeloid-derived suppressor cell (G-MDSC) dominant" cluster, with high number of HLA-DR- CD14- myeloid cells; subtype II, the "immune exhausted" cluster, with high exhausted T-cell and dendritic-cell infiltration; and subtype III, the "immune desert" cluster, with few immune cells. Immune cell-rich subtypes (subtype I and II) were characterized by IDH mutation, pathologic high grade, and peritumoral edema, while subtype I cases were exclusively featured by myxoid transformation. In clinical practice involving 12 individuals who received PD-1 antibody immunotherapy, all of the 3 cases with controlled diseases were retrospectively classified as subtype II. In mechanism, IDH mutation significantly elevated chemokine levels and immune-cell infiltration in immune-inactivated tumors. CONCLUSIONS: This study is the first to provide immune characterization of CHS, representing a major step to precise immunotherapy against this malignancy. Immunotherapy is promising for the "immune exhausted" subtype of patients with CHS.

Outcome in dedifferentiated chondrosarcoma for patients treated with multimodal therapy: Results from the EUROpean Bone Over 40 Sarcoma Study.

INTRODUCTION: The role of chemotherapy for patients with dedifferentiated chondrosarcoma (DDCS) is still under discussion. Here, we present the outcome in patients with DDCS treated with intensive chemotherapy from the EUROpean Bone Over 40 Sarcoma Study. MATERIALS AND METHODS: The chemotherapy regimen included doxorubicin, ifosfamide and cisplatin. Postoperative methotrexate was added in case of poor histological response. Toxicity was graded based on the National Cancer Institute expanded common toxicity criteria, version 2.0, and survival was analysed using Kaplan-Meier curves, log-rank tests and univariate Cox regression models. RESULTS: Fifty-seven patients with DDCS (localised, 34 [60%]; metastatic, 23 [40%]) aged 42-65 years were included. Surgical complete remission (SCR) was achieved in 36 (63%) patients. The median overall survival (OS) was 24 months (95% confidence interval, 22-25), and the 5-year OS was 39%. Patients with extremity localisation had a 5-year OS of 49% compared with 29% in patients with a central tumour (P = 0.08). Patients with localised disease had a 5-year OS of 46%, whereas patients with metastatic disease had a 5-year OS of 29% (P = 0.12). Patients in SCR had a 5-year OS of 49%, whereas patients not in SCR had a 5-year OS of 23% (P = 0.004). Chemotherapy toxicity was considerable but manageable. There was no treatment-related death, and 39 (70%) patients received ≥6 cycles of the planned nine chemotherapy cycles. CONCLUSIONS: Adding intensive chemotherapy to surgery for treatment of DDCS is feasible and shows favourable survival data compared with previous reports. With the limitations of data from a non-controlled trial, we conclude that chemotherapy could be considered in the management of patients aged >40 years.

Bacteriophage-mediated therapy of chondrosarcoma by selective delivery of the tumor necrosis factor alpha (TNFα) gene.

Chondrosarcoma is a cartilage-forming bone tumor, well known for intrinsic resistance to chemotherapy and radiotherapy. We have designed a targeted chondrosarcoma gene therapy using a bacteriophage (phage) particle to deliver therapeutic genes. Phage has no tropism for mammalian cells, allowing engineered phage to be targeted to specific cell surface receptors in cancer. We modified the phage capsid to display the RGD4C ligand on the pIII minor coat proteins to specifically bind to αvß3 or αvß5 integrin receptors. The endosomal escape peptide, H5WYG, was also displayed on recombinant pVIII major coat proteins to enhance gene delivery. Finally, a human tumor necrosis factor alpha (TNFα) therapeutic transgene expression cassette was incorporated into the phage genome. First, we found that human chondrosarcoma cells (SW1353) have high expression of αvß3, αvß5 integrin receptors, and both TNFα receptors. Targeted particle encoding a luciferase reporter gene efficiently and selectively mediated gene delivery to these cells. When SW1353 cells were treated with the targeted particle encoding a TNFα transgene, significant cell killing was evident and was associated with high expression of TNFα and apoptosis-related genes. In vivo, mice with established human chondrosarcoma showed suppression of tumors upon repetitive intravenous administrations of the targeted phage. These data show that our phage-based particle is a promising, selective, and efficient tool for targeted chondrosarcoma therapy.

Calcaneal Bone Tumors.

Bone tumors of the foot are an uncommon finding. Most tumors are found incidentally on imaging and are benign. Care must be taken although due to the aggressive nature of malignant bone tumors that can occur in the calcaneus. Malignant lesions will more commonly present with symptoms of pain and swelling. Often misdiagnosed as soft tissue injuries, it is critical to be able to diagnose and treat these lesions early. Imaging plays an important role with plain films and advanced imaging. Surgical treatments can range from curettage with grafting to amputation for more aggressive lesions.

Outcomes and Patterns of Care in Adult Skull Base Chondrosarcoma Patients in the United States.

BACKGROUND: Chondrosarcomas of the skull base are rare intracranial tumors of chondroid origin. The rarity of these lesions has made it difficult to form a consensus on optimal treatment regimens. The aim of this study was to provide a comprehensive analysis of prognostic factors, treatment modalities, and survival outcomes in patients with chondrosarcoma of the skull base. METHODS: Patients with diagnosis codes for chondrosarcoma of the skull base were queried from the National Cancer Database for the years 2004-2016. Outcomes were investigated using Cox univariate and multivariate regression analyses, and survival curves were generated for comparative visualization. RESULTS: A total of 718 patients with chondrosarcoma of the skull base were identified. Mean overall survival (OS) in these patients was 10.7 years. Older age and presence of metastases were associated with worsened OS. Of patients, 83.3% received surgical intervention, and both partial resection and radical resection were associated with significantly improved OS (P < 0.001). Neither radiotherapy nor chemotherapy improved OS; however, patients who received proton-based radiation and patients who received high-dose radiation (≥6000 cGy) had significantly improved OS compared with patients who received traditional radiation. CONCLUSIONS: In the largest study to our knowledge of skull base chondrosarcoma to date, both partial resection and radical resection significantly improved OS, thus supporting the goal of maximal safe resection to preserve vital neurovascular structures without sacrificing outcome. In patients who received radiotherapy, proton-based modalities and high-dose radiation were associated with increased OS.

Incidence, Management, and Outcomes of Adult Patients with Spinal Chondrosarcoma in the United States.

OBJECTIVE: Spinal chondrosarcomas are rare primary malignant neoplasms composed of cartilage-producing cells. They are slow-growing but locally aggressive lesions that have high rates of recurrence and progression after treatment. We provide the largest comprehensive analysis of prognostic factors, treatment modalities, and survival outcomes in patients with spinal chondrosarcoma using a large, prospectively collected national database. METHODS: Patients with diagnosis codes specific for chondrosarcoma of the spine, sacrum, and coccyx were queried from the National Cancer Database (NCDB) during 2004-2016. Outcomes were investigated using Cox univariate and multivariate regression analyses, and survival curves were generated for comparative visualization. RESULTS: A total of 1843 individuals were identified with a diagnosis of chondrosarcoma, 82.1% of which were at the sacrum or coccyx and 17.9% at the spine. The mean overall survival of patients in our cohort was 7.91 years. Increased age, larger tumor, dedifferentiated histology, and presence of metastases were associated with worsened overall survival. Regarding management, 77.7% of patients received surgical intervention and both partial and radical resection were associated with significantly improved overall survival (P < 0.001). Neither radiotherapy nor chemotherapy administration improved overall survival; however, among patients who received radiation, those who received higher-dose radiation had significantly improved overall survival compared with those who received lower-dose radiation. CONCLUSIONS: Surgical resection significantly improves overall survival in patients with spinal chondrosarcoma. In those patients receiving radiation, those who receive high doses have improved overall survival compared with those who receive lower doses. Further studies into optimal radiation modality and doses are required.

Chondrosarcoma.

Chondrosarcoma is the second most common primary bone tumor, with >90% of cases representing the primary conventional subtype. In addition to arising de novo, conventional chondrosarcoma can arise secondary to a benign underlying lesion, such as enchondroma or osteochondroma. Symptoms are often characterized by focal, dull, aching pain to the affected region. Grade is a well-recognized prognostic factor in these tumors. Grade I lesions/atypical cartilaginous tumors rarely metastasize, rarely recur, and have a 10-year survival rate of >80%. By contrast, grade III lesions are associated with a poor prognosis with the highest local recurrence rates, a lung metastasis rate of >50%, and a 10-year survival rate of <30%. The standard treatment of high-grade conventional chondrosarcoma is complete surgical resection with wide margin. However, low-grade lesions may be amenable to curettage plus or minus adjuvant local treatment. Conventional chondrosarcoma does not respond to chemotherapy or standard radiation doses. Adjuvant treatment can be beneficial for some subtypes such as chemotherapy for dedifferentiated and mesenchymal chondrosarcoma and radiation additionally for mesenchymal chondrosarcoma. Emerging radiation technologies may also play a useful role in treating tumors in anatomically complex areas such as the spine or pelvis.

Relevance of the combination of external beam radiotherapy with the hypoxia-activated prodrug ICF05016 in an experimental model of extraskeletal myxoid chondrosarcoma.

Currently, there is no gold standard treatment for Extraskeletal Myxoid Chondrosarcomas (EMC) making wide margin surgical resection the most effective alternative treatment. Nevertheless, in previous preclinical studies our lab demonstrated the potential of the hypoxia-activated prodrug (HAP) ICF05016 on EMC murine model inoculated with the H-EMC-SS human cell line. The aim of this study was to assess, in vivo, the relevance of the combination of this HAP with External Beam Radiotherapy (EBR). Firstly EMC-bearing mice were treated with 6 Gy or 12 Gy of EBR (single 6 MV photon). Then for combination of HAP and EBR, animals received 6 doses of ICF05016 (46.8 µmol/kg, intravenously) at 4-day intervals, with 6 Gy EBR performed 24 h after the 3rd dose of HAP. Animals were monitored throughout the study for clinical observations (tumour growth, side effects) and survival studies were performed. From tumour samples, PCNA, Ki-67 and p21 expressions were used as markers of proliferation and cell cycle arrest. Statistical significances were determined using Kruskall-Wallis and log rank tests. The radiosensitivity of the EMC model was demonstrated at 12 Gy with significant inhibition of tumour growth. Then, the HAP strategy potentiated EBR efficacy at a lower dose (6 Gy) by improving survival without generating side effects. Thus, results of this study showed the potential interest of ICF05016 for the combination with EBR in the management of EMC.

[Tumors affecting the temporomandibular joint - a literature review]. / Tumeurs de l'articulation temporomandibulaire ­ revue de la littérature.

Benign and malign tumors can affect the temporomandibular joint (TMJ) as any other articulation. Nevertheless, TMJ tumors are rare and mostly benign. Their clinical expression is varied including symptomatology similar to TMJ dysfunctional disorders, otologic or neurologic pathologies. In some cases, they remain totally asymptomatic. Hence, diagnosis is difficult since the symptomatology can be misleading with TMJ dysfunctional disorders or otologic disorders wrongly diagnosed. There is thus frequently a long delay between symptoms onset and diagnosis. The great variety of TMJ lesions explains the wide range of possible treatment modalities, mostly based on surgery. We provide here a review of the lesions originating from the TMJ. Tumoral or cystic mandibular lesion affecting the TMJ through local extension will not be discussed. Osteoma, osteoid osteoma, osteoblastoma, chondroma, osteochondroma, chondroblastoma, tenosynovial giant cell tumors, giant cell lesions, non-ossifying fibroma, hemangioma, lipoma or Langerhans cell histiocytosis are all possible diagnosis among the benign tumors found in the TMJ. Pseudotumors include synovial chondromatosis and aneurysmal bone cyst. Finally, malign tumors of the TMJ include mainly sarcomas (osteosarcoma, chondrosarcoma, synovial sarcoma, Ewing sarcoma, and fibrosarcoma), but also multiple myeloma and secondary metastases. We will review the clinical, radiological and histological aspects of each of these lesions. The treatment and the recurrence risk will also be discussed.

Diagnoses, treatment, and oncologic outcomes in patients with calcaneal malignances: Case series, systematic literature review, and pooled cohort analysis.

BACKGROUND AND OBJECTIVES: Malignant tumors of the calcaneus are rare but pose a treatment challenge. AIMS: (1) describe the demographics of calcaneal malignancies in a large cohort; (2) describe survival after amputation versus limb-salvage surgery for high-grade tumors. METHODS: Study group: a "pooled" cohort of patients with primary calcaneal malignancies treated at two cancer centers (1984-2015) and systematic literature review. Kaplan-Meier analyses described survival across treatment and diagnostic groups; proportional hazards modeling assessed mortality after amputation versus limb salvage. RESULTS: A total of 131 patients (11 treated at our centers and 120 patients from 53 published studies) with a median 36-month follow-up were included. Diagnoses included Ewing sarcoma (41%), osteosarcoma (30%), and chondrosarcoma (17%); 5-year survival rates were 43%, 73% (70%, high grade only), and 84% (60%, high grade only), respectively. Treatment involved amputation in 52%, limb salvage in 27%, and no surgery in 21%. There was no difference in mortality following limb salvage surgery (vs. amputation) for high-grade tumors (HR 0.38; 95% CI 0.14-1.05), after adjusting for Ewing sarcoma diagnosis (HR 5.15; 95% CI 1.55-17.14), metastatic disease at diagnosis (HR 3.88; 95% CI 1.29-11.64), and age (per-year HR 1.04; 95% CI 1.02-1.07). CONCLUSIONS: Limb salvage is oncologically-feasible for calcaneal malignancies.

Economics of the Management of Craniospinal Chordoma and Chondrosarcoma and the feasibility of the bundled payment model.

BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) created a new reimbursement model "Bundled Payment for Care Improvement (BPCI)" which reimburses providers a predetermined payment in advance to cover all possible services rendered within a certain time window. Chordoma and Chondrosarcoma are locally aggressive malignant primary bony tumors. Treatment includes surgical resection and radiotherapy with substantial risk for recurrence which necessitates monitoring and further treatment. We assessed the feasibility of the BPCI model in these neurosurgical diseases. METHODS: We selected patients with chordoma/chondrosarcoma from inpatient admission table using the International Classification of Disease, 9th (ICD-9), and 10th (ICD-10) revision codes. We collected the patients' demographics and insurance type at the index hospitalization. We recorded the following outcomes length of stay, total payment, discharge disposition, and complications for the index hospitalization. For post-discharge, we collected the 30 days and 3/6/12 months inpatient admission, outpatient service, and medication refills. Continuous variables were summarized by means with standard deviations, median with interquartile and full ranges (minimum-maximum); Continuous outcomes were compared by nonparametric Wilcoxson rank-sum test. All tests were 2-sided with a significance level of 0.05. Statistical data analysis was performed in SAS 9.4 (SAS Institute, Inc, Cary, NC). RESULTS: The population size was 2041 patients which included 1412 patients with cranial (group1), 343 patients with a mobile spine (group 2), and 286 patients with sacrococcygeal (group 3) chordoma and chondrosarcoma. For index hospitalization, the median length of stay (days) was 4, 6, and 7 for groups 1, 2, and 3 respectively (P<.001). The mean payments were ($58,130), ($84,854), and ($82,440), for groups 1, 2, and 3 respectively (P=.02). The complication rates were 30%, 35%, and 43% for groups 1, 2, and 3 respectively (P<.001). Twelve months post-discharge, the hospital readmission rates were 44%, 53%, and 65% for groups 1, 2, and 3, respectively (P<.001). The median payments for this period were ($72,294), ($76,827), and ($101,474), for groups 1, 2, and 3, respectively (P <.001). CONCLUSION: The management of craniospinal chordoma and chondrosarcoma is costly and may extend over a prolonged period. The success of BPCI requires a joint effort between insurers and hospitals. Also, it should consider patients' comorbidities, the complexity of the disease. Finally, the adoptionof quality improvement programs by hospitals can help with cost reduction.

A multimodal treatment of carbon ions irradiation, miRNA-34 and mTOR inhibitor specifically control high-grade chondrosarcoma cancer stem cells.

BACKGROUND AND PURPOSE: High-grade chondrosarcomas are chemo- and radio-resistant cartilage-forming tumors of bone that often relapse and metastase. Thus, new therapeutic strategies are urgently needed. MATERIAL AND METHODS: Chondrosarcoma cells (CH-2879) were exposed to carbon-ion irradiation, combined with miR-34 mimic and/or rapamycin administration. The effects of treatment on cancer stem cells, stemness-associated phenotype, radioresistance and tumor-initiating properties were evaluated. RESULTS: We show that high-grade chondrosarcoma cells contain a population of radioresistant cancer stem cells that can be targeted by a combination of carbon-ion therapy, miR-34 mimic administration and/or rapamycin treatment that triggers FOXO3 and miR-34 over-expression. mTOR inhibition by rapamycin triggered FOXO3 and miR-34, leading to KLF4 repression. CONCLUSION: Our results show that particle therapy combined with molecular treatments effectively controls cancer stem cells and may overcome treatment resistance of high-grade chondrosarcoma.

Bone Tumors: Primary Bone Cancers.

The three most common primary bone cancers are osteosarcoma, Ewing sarcoma, and chondrosarcoma. Osteosarcoma occurs most often in children and young adults, with a peak incidence at ages 10 to 14 years. It also can occur later in life due to malignant transformation of benign bone lesions. Osteosarcoma occurs most commonly around the knee, but can occur in other bones. Management varies depending on tumor characteristics and involves chemotherapy and surgery. Ewing sarcoma is most common in teenagers. It occurs most commonly in long bones but can occur in the pelvis and other bones. Management involves surgical resection when possible, along with chemotherapy and occasionally radiation therapy. Chondrosarcoma typically occurs in patients 40 years and older. It can occur as a primary tumor or from malignant transformation of benign bone tumors. Chondrosarcomas are relatively resistant to chemoradiation, so surgery is the standard therapy. When any of these tumors is suspected, patients should be instructed to avoid weight-bearing on the affected extremity to help prevent pathologic fracture while evaluation is completed. Imaging with x-rays and occasionally magnetic resonance imaging study are the initial diagnostic steps. If imaging suggests a primary bone cancer, prompt referral to an orthopedic oncology subspecialist is indicated.

Therapeutic strategy for tracheal chondrosarcoma: report of two cases.

Primary chondrosarcoma of the trachea is an extremely rare tumor. We report two cases of tracheal chondrosarcoma describing the role of surgical and conservative treatment. Endoscopic treatment with rigid bronchoscopy was performed in both patients to restore airway patency and obtain histological specimens for diagnosis. One of the patients subsequently underwent successful tracheal resection and reconstruction. The other patient, who had a contraindication to surgical treatment due to associated diseases underwent iterative endoscopic LASER treatment and is alive three years after the first diagnosis. Surgical treatment remains the treatment of choice of tracheal chondrosarcoma. When surgery is contraindicated endoscopic treatment may allow relatively longterm survival due to the slow growth of these tumors.