Chordoma Patients Research Articles

A novel energy layer optimization framework for spot-scanning proton arc therapy.

Spot-scanning proton arc therapy (SPAT) is an emerging modality to improve plan conformality and delivery efficiency. A greedy and heuristic method is proposed in the existing SPAT algorithm to select energy layers and sequence energy switching with gantry rotation, which does not promise optimality in either dosimetry or efficiency. We aim to develop a method to solve the energy layer switching and dosimetry optimization problems in an integrated framework for SPAT. In an integrated approach, energy layer optimization for spot-scanning proton arc therapy (ELO-SPAT) is formulated with a dose fidelity term, a group sparsity regularization, a log barrier regularization, and an energy sequencing (ES) penalty. The combination of L2,1/2-norm group sparsity regularization and log barrier function allows one energy layer being selected per control point. The ES regularization term sorts the delivery sequence from high energy to low energy to reduce the total energy layer switching time (ELST) and subsequently the total delivery time. Within the ES penalty, the gradient of layer weights between adjacent beams is first calculated along beam direction and then along energy direction. The gradients indicate energy switch patterns between two adjacent beams. The time-wise costly energy switch-up is more heavily penalized in the ES term. This ELO-SPAT method was tested on one frontal base-of-skull (BOS) patient, one chordoma (CHDM) patient with a simultaneous integrated boost, one bilateral head-and-neck (H&N) patient, and one lung (LNG) patient. We compared ELO-SPAT with intensity-modulated proton therapy (IMPT) using discrete beams and SPArc by Ding et al. For the two arc algorithms, both the plans with and without energy sequencing were created and compared. Energy layer optimization for spot-scanning proton arc therapy reduced the runtime of optimization by 84% on average compared with the greedy SPArc method. In both the ELO-SPAT plans with and without ES, one energy layer per control point was selected. Without ES regularization, the energy sequence was arbitrary, with around 40-60 switch-up for the tested cases. After adding ES regularization, the number of energy switch-up was reduced to less than 20. Compared with the energy sequenced SPArc plans, the ELO-SPAT plans with ES led to 24% less total ELST for synchrotron plans and 14% less for cyclotron plans. Both the ELO-SPAT and SPArc plans achieved better sparing compared with the IMPT plans for most Organs-at-risks (OARs), with or without ES. Without ES, the ELO-SPAT plans achieved further improvement of the OARs compared with the SPArc plans, with an averaged reduction of OAR [Dmean, Dmax] by [1.57, 3.34] GyRBE. Adding the ES regularization degraded the plan quality, but the ELO-SPAT plans still had comparable or slightly better sparing than the SPArc plans with ES, with an averaged reduction of OAR [Dmean, Dmax] by [1.42, 2.34] GyRBE. We developed a computationally efficient spot-scanning proton arc optimization method, which solved energy layer selection and sequencing in an integrated framework, generating plans with good dosimetry and high delivery efficiency.

The Role of Radiotherapy for Chordoma Patients Managed With Surgery: Analysis of the National Cancer Database.

Retrospective review. To determine if adjuvant radiation therapy (RT) improves overall survival (OS) following surgical resection of chordomas. The role of RT for the treatment of chordomas remains incompletely described. Previous studies have not found adjuvant RT to improve OS, but these studies did not group patients based on surgical margin status or radiation dose or modality. We used the National Cancer Database to investigate the role of RT in chordomas following surgical resection. Patients were stratified based on surgical margin status (positive vs. negative). Utilizing the Kaplan-Meier method, OS was compared between treatment modalities (surgical resection alone, therapeutic RT alone, and surgical resection plus therapeutic RT). OS was subsequently compared between patients treated with palliative dose (<40 Gy), low dose (40-65 Gy), and high dose (>65 Gy) RT. Similarly, OS was compared between advanced RT modalities including proton beam therapy (PBT) and intensity-modulated radiation therapy (IMRT), stereotactic radiosurgery (SRS), and external beam radiation therapy (EBRT). A multivariable model was used to determine adjusted variables predictive of mortality. One thousand four hundred seventy eight chordoma patients were identified; skull base (n = 567), sacral (n = 551), and mobile spine (n = 360). Surgical resection and therapeutic adjuvant RT improved 5-year survival in patients with positive surgical margins (82% vs. 71%, P = 0.03). No clear survival benefit was observed with the addition of adjuvant RT in patients with negative surgical margins. High dose RT was associated with improved OS compared with palliative and low dose RT (P < 0.001). Advanced RT techniques and SRS were associated with improved OS compared with EBRT. In the multivariate analysis high dose advanced RT (>65 Gy) was superior to EBRT. Patients with positive surgical margins benefit from adjuvant RT. Optimal OS is associated with adjuvant RT administered with advanced techniques and cumulative dose more than 65 Gy. 4.

Comparison of Wide Margin and Inadequate Margin for Recurrence in Sacral Chordoma: A Meta-Analysis.

.: A meta-analysis. .: The goal of this study was to accurately evaluate the risk ratio (RR) of recurrence in chordoma patients with wide margin after removing the tumors using surgery, compared with inadequate margin (intralesional or marginal). .: As a rare malignant bone cancer, the more effective treatment for sacral chordoma is still surgical resection. However, there is no convincing evidence and risk ratio about sacral chordoma patients would be benefit from which kind of surgical margin. .: We searched the PubMed, Cochrane Library, Web of Science, and EMBASE from inception to December 2018. The heterogeneity analysis and calculation of the pooled risk ratio were performed using RevMan 5.3 software. The assessment of publication bias and sensitivity analysis was conducted using StataSE 15.1 software. The protocol for this meta-analysis was registered on International prospective register of systematic reviews (PROSPERO, CRD42019127441). .: Twelve studies with a total of 436 patients who met the inclusion criteria were included. The pooled results indicated that patients in the wide group had lower recurrence rate than those in the inadequate group (RR = 0.42, 95% confidence interval [CI] 0.31-0.57; P < 0.001). And patients in the wide group had lower mortality rate than those in the inadequate group (RR = 0.49, 95% CI 0.26-0.91; P = 0.02). No significant differences in the risk of mortality were found between relapsed patients in the two groups (RR = 0.64, 95% CI 0.35-1.15; P = 0.13). .: In sacral chordoma patients, wide margin is associated with low recurrence risk, when it is feasible, a wide excision should be considered appropriate for sacrum chordoma. 2.

Peri-operative prognostic factors for primary skull base chordomas: results from a single-center cohort.

Skull base chordomas (SBC) are rare malignant tumors and few factors have been found to be reliable markers for clinical decision making and survival prognostication. The aim of the present work was to identify specific prognostic factors potentially useful for the management of SBC patients. A retrospective review of all the patients diagnosed and treated for SBC at the Fondazione IRCCS Istituto Neurologico "Carlo Besta" between January 1992 and December 2017 has been performed. Survival analysis was performed and a logistic regression model was used. Statistically significant predictors were rated based on their log odds in order to preliminarily build a personalized grading scale-the Peri-Operative Chordoma Scale (POCS). Fifty-nine primary chordoma patients were included. The average follow-up from the first treatment was 82.6months (95% CI, 65.5-99.7). POCS was built over PFS and MR contrast enhancement (intense vs mild/no, value 4), preoperative motor deficit (yes vs no, value 3), and the development of any postoperative complications (yes vs no, value 2). POCS ranges between 0 and 9, with higher scores being associated with reduced likelihood of survival and progression-free state. Our results show that preoperative clinical symptoms (motor deficits), surgical features (extent of tumor resection and surgeon's experience), development of postoperative complications, and KPS decline represent significant prognostic factors. The degree of MR contrast enhancement significantly correlated to both OS and PFS. We also preliminarily developed the POCS as a prognostic grading scale which may help neurosurgeons in the personalized management of patients undergoing potential adjuvant therapies.

A Series of 62 Skull Base Chordomas in Pediatric and Adolescent Patients: Clinical Characteristics, Treatments, and Outcomes.

Skull base chordomas in pediatric and adolescent patients are rare and challenging for surgeons. Well-specified diagnosis and treatment are of great value for the long-term control of chordoma. This study summarizes well-followed pediatric and adolescent chordoma (PAC) patients treated in a single Asian center. PAC patients were enrolled. Data collected included clinical presentation, tumor volume, texture, surgical approach, pathology, complications, adjuvant radiotherapy (RT), and long-term outcomes. Sixty-two patients were identified from a total of 516 skull base chordoma patients (12%). Diplopia was the most prominent complaint (30%). The craniocervical junction area was the most common location (41.8%) and had the highest proportion of large tumors. The gross total resection (GTR) rate was 20.3%. The GTR rate was lowest for tumors located in the craniocervical junction area. Thirty-eight cases experienced surgical complications. Of note, there was a significant difference in the complication rate between endoscopic approaches (22.7%) and open approaches (57.9%) (P = 0.005). The mean follow-up was 66.5 months. The GTR group showed better survival compared with the non-GTR group (P = 0.043). Metastases were found in two cases. No significant difference in the overall survival (OS) time was found between the group with RT and the group without RT (P = 0.559). A higher proportion of PAC patients than previously reported exist in the population in Asia, and the metastatic rate is lower. GTR predicts excellent long-term control of the disease. RT should be considered on an individual basis.

Aberrant CDK9 expression within chordoma tissues and the therapeutic potential of a selective CDK9 inhibitor LDC000067.

Objectives: Chordomas are slow-growing malignancies that commonly affect vital neurological structures. These neoplasms are highly resistant to current chemotherapeutic regimens and often recur after surgical intervention. Therefore, there is an urgent need to identify molecular targets and more robust drugs to improve chordoma patient outcomes. It is well accepted that cyclin-dependent protein kinase 9 (CDK9) has tumorigenic roles in various cancers; however, the expression and significance of CDK9 in chordoma remains unknown.Methods: Expression of CDK9 in chordoma cell lines and tumor tissues was examined by Western blot and immunohistochemistry (IHC). The correlation between CDK9 expression in patient tissues and clinical prognosis was analyzed. The functional roles of CDK9 in chordoma were investigated after the addition of small interfering RNA (siRNA) and CDK9 inhibitor (LDC000067). Cell growth and proliferation were assessed with MTT and clonogenic assays. The effect of CDK9 inhibition on chordoma cells was further evaluated with a three-dimensional (3D) cell culture model which mimics the in vivo environment.Results: CDK9 was expressed in both chordoma cell lines and chordoma tissues. High- expression of CDK9 correlated with recurrence and poor outcomes for chordoma patients. CDK9 silencing with siRNA decreased growth and proliferation of chordoma cells and lowered levels of Mcl-1 and RNA polymerase II (RNAP II) phosphorylation. Pharmacological inhibition of CDK9 with the small molecular inhibitor LDC000067 reduced cell growth, supported apoptosis, suppressed cell colony formation in a clonogenic assay, and decreased spheroid growth in 3D culture.Conclusion: We demonstrate that CDK9 expression in chordoma correlates with patient outcome, and, when inhibited, chordoma cell growth and proliferation significantly decreases. Taken together, these results support CDK9 as an emerging potential target in chordoma therapy.

Subarachnoid pump implant for the treatment of sacrococcygeal chordoma patient pain. Case report

Subarachnoid pump implant for the treatment of sacrococcygeal chordoma patient pain. Case report

Endoscopic Resection of Clival Chordoma: A Tertiary Care Experience.

The primary management of the rare tumor chordoma is always surgical. This study indicates the advantage of endoscopic approach for clival chordoma resection. This is a Retrospective case series of 7 endoscopically operated clival chordoma patients between May 2015 and April 2018 in our tertiary care hospital. 5 patients presented with primary disease and 2 were recurrent disease cases. Endoscopic endonasal transphenoidal approach with wide clearance of margins of tumor were performed in all 7 cases. High energy photon radiotherapy were delivered to all. All patients with primary disease as well as recurrent disease had no evidence of disease 24-32months post surgery. Endoscopic endonasal transphenoidal approach for clival chordoma provides a safe and reliable tumor resection. This less invasive surgery can be considered as an alternative to traditional surgical technique with reduced morbidity. This approach represents a combination of various endoscopic surgical techniques which are minimally invasive and can be applied to ventral skull base surgery.

RARE-29. AZD8055 ENHANCES IN VIVO EFFICACY OF AFATINIB IN CHORDOMAS

Abstract INTRODUCTION Chordomas are rare, locally aggressive bone tumors that arise in cranial base, mobile spine, and sacrum. Currently, there are no FDA-approved therapies for chordoma patients, thus there is a high unmet need to develop effective treatments. In this study, we aim to evaluate the anti-tumor efficacy of small molecule inhibitors that target crucial oncogenic pathways in chordoma, as single agents or in combination, to identify novel therapies with the greatest translation potential. METHODS A panel of small molecule compounds that had exhibited in vitro efficacy against human chordoma cell lines or target known chordoma drivers was screened in vivo against patient-derived xenograft (PDX) models of chordoma, and their efficacy was further evaluated using chordoma cell lines and xenograft models. RESULTS The in vivo activity of compounds identified in a NIH Chemical Genomics Center screen utilizing chordoma cell lines, together with inhibitors of c-MET and PDGFR, were evaluated in PDX models of chordoma that were previously described or recently established for this study. Inhibitors of EGFR (BIBX1382, erlotinib and afatinib), c-MET (crizotinib) or mTOR (AZD8055) significantly inhibited tumor growth in vivo but did not induce tumor regression. Co-inhibition of EGFR and c-MET using erlotinib and crizotinib synergistically reduced cell viability in chordoma cell lines but did not result in enhanced in vivo activity. Co-inhibition of EGFR and mTOR pathways using afatinib and AZD8055 synergistically reduced cell viability in chordoma cell lines. Importantly, co-inhibition of EGFR and mTOR also synergistically suppressed tumor growth in vivo, showing improved disease control. CONCLUSION Single inhibition of EGFR, c-MET or mTOR suppresses chordoma growth both in vitro and in vivo. Co-inhibition of EGFR and mTOR synergistically inhibits chordoma growth in a range of preclinical models. The insights gained from our study provide a novel combination therapeutic strategy for patients with chordoma.

Cost-effectiveness of proton therapy in treating base of skull chordoma.

While proton beam therapy (PBT) can offer increased sparing of healthy tissue, it is associated with large capital costs and as such, has limited availability. Furthermore, it has not been well established whether PBT has significant clinical advantages over conventional volumetric modulated arc therapy (VMAT) for all tumour types. PBT can potentially offer improved clinical outcomes for base of skull chordoma (BOSCh) patients compared with photon (X-ray) therapy, however the cost-effectiveness of these treatments is unclear. In this study, the cost-effectiveness of PBT in the treatment of BOSCh patients is assessed, based on an analysis of comparative radiotherapy treatment plans using a radiobiological Markov model. Seven BOSCh patients had treatment plans for the delivery of intensity modulated proton therapy and VMAT retrospectively analysed. The patient outcome (in terms of tumour local control and normal tissue complications) after receiving each treatment was estimated with a radiobiological Markov model. In addition, the model estimated the cost of both the primary treatment and treating any resultant adverse events. The incremental cost-effectiveness ratio (ICER) was obtained for each patient. PBT was found to be cost-effective for 5 patients and cost-saving for 2. The mean ICER was AUD$1,990 per quality adjusted life year gained. Variation of model parameters resulted in the proton treatments remaining cost-effective for these patients. Based on this cohort, PBT is a cost-effective treatment for patients with BOSCh. This supports the inclusion of PBT for BOSCh in the Medicare Services Advisory Committee 1455 application.

RBE-weighted doses in target volumes of chordoma and chondrosarcoma patients treated with carbon ion radiotherapy: Comparison of local effect models I and IV

Background and purposeTo compare the relative biological effectiveness (RBE)-weighted dose distributions in the target volume of chordoma and chondrosarcoma patients when using two different versions of the local effect model (LEM I vs. IV) under identical conditions. Materials and methodsThe patient collective included 59 patients treated with 20 fractions of carbon ion radiotherapy for chordoma and low-grade chondrosarcoma of the skull base at the Helmholtzzentrum für Schwerionenforschung (GSI) in 2002 and 2003. Prescribed doses to the planning target volume (PTV) were 60 (n = 49), 66 (n = 2) and 70 (n = 8) Gy (RBE). The original treatment plans that were initially biologically optimized with LEM I, were now recalculated using LEM IV based on the absorbed dose distributions. The resulting RBE-weighted dose distributions were quantitatively compared to assess the clinical impact of LEM IV relative to LEM I in the target volume. ResultsLEM IV predicts 20–30 Gy (RBE) increased maximum doses as compared to LEM I, while minimum doses are decreased by 2–5 Gy (RBE). Population-based mean and median doses deviated by less than 2 Gy (RBE) between both models. ConclusionsLEM I and LEM IV-based RBE-weighted doses in the target volume may be significantly different. Replacing the applied model in patient treatments may therefore lead to local over- or underdosages in the tumor. If LEM IV is to be tested clinically, comparisons of the RBE-weighted dose distributions of both models are required for the individual patients to assess whether the LEM IV-plan would also be acceptable and prescribed dose as well as clinical outcome data have to be carefully reassessed.

Long and Very-Long-Chain Ceramides Correlate with A More Aggressive Behavior in Skull Base Chordoma Patients.

Background: Skull base chordomas are rare tumors arising from notochord. Sphingolipids analysis is a promising approach in molecular oncology, and it has never been applied in chordomas. Our aim is to investigate chordoma behavior and the role of ceramides. Methods: Ceramides were extracted and evaluated by liquid chromatography and mass spectrometry in a cohort of patients with a skull base chordoma. Clinical data were also collected and correlated with ceramide levels. Linear regression and correlation analyses were conducted. Results: Analyzing the association between ceramides level and MIB-1, total ceramides and dihydroceramides showed a strong association (r = 0.7257 and r = 0.6733, respectively) with MIB-1 staining (p = 0.0033 and p = 0.0083, respectively). Among the single ceramide species, Cer C24:1 (r = 0.8814, p ≤ 0.0001), DHCer C24:1 (r = 0.8429, p = 0.0002) and DHCer C18:0 (r = 0.9426, p ≤ 0.0001) showed a significant correlation with MIB-1. Conclusion: Our lipid analysis showed ceramides to be promising tumoral biomarkers in skull base chordomas. Long- and very-long-chain ceramides, such as Cer C24:1 and DHCer C24:1, may be related to a prolonged tumor survival and aggressiveness, and the understanding of their effective biological role will hopefully shed light on the mechanisms of chordoma radio-resistance, tendency to recur, and use of agents targeting ceramide metabolism.

76. High dose radiation therapy improves survival for chordoma patients with positive surgical margins

BACKGROUND CONTEXT The role of radiation therapy (RT) for the treatment of axial chordomas remains controversial. Previous large database reviews have not found adjunct RT to improve overall survival, but these studies did not stratify based on high/low dose RT, the modality of RT, or the patient's surgical margin status. PURPOSE We investigated the National Cancer Database (NCDB) to determine if high dose RT improves survival in patients with positive vs negative surgical margins. Additionally, the study compares the 5-year survival between patient's treated with high vs low dose RT and advanced vs conventional delivery methods. STUDY DESIGN/SETTING Retrospective study. PATIENT SAMPLE A total of 1,480 chordoma patients. OUTCOME MEASURES Five-year overall survival. METHODS A total of 1,480 patients were identified in the NCDB between 2004 and 2015 with a histologically confirmed axial chordoma. Survival analysis was performed using the Kaplan Meier method. The 5-year survival was compared between surgical resection alone and surgical resection and adjunct therapeutic RT for the overall cohort, patients with positive surgical margins, and patients with negative surgical margins. Therapeutic RT was defined as a radiation dose greater than 65Gy. For patients treated with RT, the 5-year survival was compared between palliative dose ( 65Gy) RT. Similarly, 5-year survival was compared between proton beam therapy (PBT), stereotactic radiosurgery (SRS), intensity-modulated radiation therapy (IMRT), and conventional external beam radiation therapy (EBRT). A multivariable analysis was performed to determine independent prognosticators associated with 5-year overall survival. RESULTS The cohort included 1,480 chordoma patients; skull base (n=569), sacral (n=551), mobile spine (n=360). The 5-year survival for the entire cohort was 76%. The survival for patients treated with surgical resection and adjunct therapeutic RT was greater than surgery alone (85% vs 80%, p=0.04). Therapeutic adjunct RT improved survival compared to surgery alone in the setting of positive surgical margins (82% vs 71%, p=0.03). In the setting of negative surgical margins adjunct RT did not statistically improve survival (p=0.33). Radiation dose >65Gy improved survival when compared to radiation dose between 40-65Gy (85% vs 69%, p CONCLUSIONS Adjunct RT (dose >65Gy) was associated with improved survival for patients with positive surgical margins; however, a survival benefit was not observed for patients with negative surgical margins. High dose RT and advanced radiation techniques, specifically PBT, were associated with improved 5-year survival. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

Ambient neutron and photon dose equivalent H*(10) around a pencil beam scanning proton therapy facility.

To measure leakage ambient dose equivalent H*(10) from stray secondary neutron and photon radiation around proton therapy (PT) facility and evaluate adequacy of shielding design. H*(10) measurement were carried out at 149 locations around cyclotron vault (CV), beam transport system (BTS) and first treatment room (GTR3) of a multiroom PT facility using WENDI-II and SmartIon survey meter. Measurement were performed under extreme case scenarios wherein maximum secondary neutrons and photons were produced around CV, BTS and GTR3 by stopping 230MeV proton of 300nA on beam degrader, end of BTS and isocenter of GTR3. Weekly time average dose rate (TADR) were calculated from H*(10) value measured at selective hot spots by irradiating actual treatment plans of mix clinical sites. The maximum total H*(10) were within 2 µSv/hr around CV, 5 µSv/hr around outer wall of BTS which increases up to 62 µSv/hr at the end of inside BTS corridor. Maximum H*(10) of 20.8 µSv/hr in treatment control console (P125), 23.4 µSv/hr behind the common wall between GTR3 and GTR2 (P132) and 25.7 µSv/hr above isocenter (P99) were observed around GTR3. Reduction of beam current from 6 to 3 nA and 1 nA at nozzle exit lead to decrease in total H*(10) at P125 from 20.8 to 11.35 and 4.62 µSv/hr. In comparison to extreme case scenario, H*(10) value at P125, P132 and P99 from clinically relevant irradiation parameters were reduce by a factor ranging from 8.6 for high range cube to 46.4 for brain clinical plan. The maximum weekly TADR per fraction was highest for large volume, sacral chordoma patient at 8.5 µSv/hr compare to 0.3 µSv/hr for brain patient. The calculated weekly TADR for 30 mix clinical cases and 15 fractions of 1 L cube resulted total weekly TADR of 83-84 µSv/hr at P125, P132 and P99. The maximum annual dose level at these hot spots were estimated at 4.37 mSv/Yr. We have carried out an extensive measurement of H*(10) under different conditions. The shielding thickness of our PT facility is adequate to limit the dose to occupational worker and general public within the permissible stipulated limit. The data reported here can bridge the knowledge gap in ambient dose around PT facility and can also be used as a reference for any new and existing proton facility for intercomparison and validation. First extensive investigation of neutron and photon H*(10) around PT facility and can bridge the knowledge gap on ambient dose.

The Therapeutic Benefit of Radiotherapy for Chordoma Patients with Positive Surgical Margins

Background: The role of radiation therapy (RT) for the treatment of chordomas remains incompletely described. Previous studies have not found adjuvant RT to improve overall survival (OS), but these studies did not group patients based on surgical margin status or radiation dose or modality. We used the National Cancer Database to investigate the role of RT in chordomas. Methods: Patients were stratified based on surgical margin status (positive vs negative). Utilizing the Kaplan Meier method, OS was compared between treatment modalities (surgical resection alone, therapeutic RT alone, and surgical resection plus therapeutic adjuvant RT). OS was also compared between patients treated with palliative dose ( 65Gy) RT. Similarly, OS was compared between advanced RT modalities including proton beam therapy (PBT) and intensity-modulated radiation therapy (IMRT), stereotactic radiosurgery (SRS), and external beam radiation therapy (EBRT). A multivariable model was used to determine adjusted variables predictive of mortality. Findings: 1,478 chordoma patients were identified; skull base (n=567), sacral (n=551), and mobile spine (n=360). The 5-year survival for the entire cohort was 76%. Surgical resection and therapeutic adjuvant RT improved 5-year survival in patients with positive surgical margins (82% vs 71%, p=0·03). No clear survival benefit was observed with the addition of adjuvant RT in patients with negative surgical margins. High dose RT was associated with improved OS compared to palliative and low dose RT (p 65Gy) was superior to palliative/low dose EBRT (< 65Gy) (HR 0.52:95%CI 0.33-0.84, p=0·007). Interpretation: Patients with positive surgical margins benefit from adjuvant RT. Optimal OS is associated with adjuvant RT administered with advanced techniques and a cumulative dose >65 Gy. Funding Statement: No funding was obtained for this study. Declaration of Interests: None of the authors have any conflicts of interests pertaining to this study. Ethics Approval Statement: This study received appropriate IRB approval prior to collecting patient data.

Comprehensive Review of Cranial Chordomas Using National Databases in the USA

AimsThe management of cranial chordomas is controversial. We provide a comprehensive review of the evolving patterns of care of cranial chordomas in the USA. Materials and methodsWe analysed the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2014 for clinical characteristics and long-term survival, and the National Surgical Quality Improvement Program (NSQIP) dataset between 2005 and 2016 for perioperative characteristics and surgical morbidity. ResultsIn total, 936 patients were identified from the NCDB, 405 patients from SEER and 64 patients from the NSQIP. Most patients were men (56.2, 54.8 and 57.8% in NCDB, SEER and NSQIP, respectively) and White (80.9 and 83.2% in NCDB and SEER, respectively). Surgery was the preferred treatment modality (87.3% in NCDB and 86.2% in SEER). Surgery was carried out alone (41.8% in NCDB and 40.7% in SEER) or in combination with radiation (42.1% in NCDB and 45.4% in SEER). Proton therapy was the most common type of radiation (32.2% in NCDB), particularly after 2011. The median operative time, median hospital length and postoperative morbidity were significantly higher in chordoma patients compared with patients who underwent other skull-base procedures. The 5-year survival rate was 79.8% in NCDB and 76.9% in SEER. There was a trend towards longer survival in patients receiving surgery and radiation, which has been increasingly used since 2004. Patients younger than 60 years had a decreased risk of mortality. ConclusionsOur analysis reflects patterns of care in the USA. The use of surgery and radiation is increasing, with a trend towards longer survival. Surgery is complicated with long operative time, hospital stay and a higher rate of complications.

Abstract 2126: Development of a precision chordoma research program

Abstract Chordomas are malignant tumors of the axial skeleton that originate from remnants of the embryonic notochord. With an incidence of one per million per year, chordoma is a rare disease that accounts for 1-4% of all bone tumors and approximately 20% of primary spinal tumors. As first-line treatment, patients undergo surgical resection followed by adjuvant radiotherapy, whereas most chordomas are resistant to conventional cytotoxic drugs and there are no clinically validated molecular drug targets. To overcome the lack of effective medical treatment and to better understand chordoma biology, we have established a chordoma precision research program. Here, whole-exome or genome and transcriptome sequencing are used to determine mutational landscapes, DNA copy number profiles, and transcriptome changes in chordoma cell lines and patient samples. Additionally, large-scale functional genomic screens and (phospho-)proteomic analyses have been performed in multiple chordoma cell lines to identify new chordoma-specific vulnerabilities. Based on these multilayered datasets, we selected a panel of previously unrecognized candidate chordoma driver genes, which are currently being validated as novel therapeutic targets using genetic and pharmacologic approaches. In addition to this unbiased approach, we seek to inhibit the embryonic transcription factor brachyury, an established driver of chordomagenesis. Although brachyury represents, in principle, a promising therapeutic target, inhibition of transcription factors remains difficult. To circumvent this challenge, we are developing Designed Ankyrin Repeat Proteins (DARPins) that specifically prevent the binding of brachyury to DNA. These DARPins are not only a valuable tool for studying chordomagenesis, but also represent a new class of molecularly targeted agents that might be used for the treatment of chordoma patients. In summary, using multi-omics data, functional genetics, and inhibition of an established chordoma driver, we are working towards a better understanding of chordoma biology and the development of new therapeutic approaches. Updated results of the precision chordoma research program will be presented. Citation Format: Marie Groth, Jana Kress, Matea Hajnic, Joana Marinho, Kevin Mellert, Thomas F. Barth, Peter Möller, Birgit Dreier, Andreas Plückthun, Claudia Scholl, Stefan Fröhling. Development of a precision chordoma research program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2126.

Near-Infrared Optical Contrast of Skull Base Tumors During Endoscopic Endonasal Surgery.

Near-infrared (NIR) tumor contrast is achieved through the "second-window ICG" technique, which relies on passive accumulation of high doses of indocyaninegreen (ICG) in neoplasms via the enhanced permeability and retention effect. To report early results and potential challenges associated with the application of second-window ICG technique in endonasal endoscopic, ventral skull-base surgery, and to determine potential predictors of NIR signal-to-background ratio (SBR) using endoscopic techniques. Pituitary adenoma (n=8), craniopharyngioma (n=3), and chordoma (n=4) patients received systemic infusions of ICG (5 mg/kg) approximately 24 h before surgery. Dual-channel endoscopy with visible light and NIR overlay were photodocumented and analyzed post hoc. All tumors (adenoma, craniopharyngioma, chordoma) demonstrated NIR positivity and fluoresced with an average SBR of 3.9±0.8, 4.1±1.7, and 2.1±0.6, respectively. Contrast-enhanced T1 signal intensity proved to be the single best predictor of observed SBR (P=.0003). For pituitary adenomas, the sensitivity, specificity, positive predictive value, and negative predictive value of NIR-guided identification of tumor was 100%, 20%, 71%, and 100%, respectively. In this preliminary study of a small set of patients, we demonstrate that second-window ICG can provide NIR optical tumor contrast in 3 types of ventral skull-base tumors. Chordomas demonstrated the weakest NIR signal, suggesting limited utility in those patients. Both nonfunctional and functional pituitary adenomas appear to accumulate ICG, but utility for margin detection for the adenomas is limited by low specificity. Craniopharyngiomas with third ventricular extension appear to be a particularly promising target given the clean brain parenchyma background and strong SBR.

Abstract 2723: Defective homologous recombination DNA repair as therapeutic target in advanced chordoma

Abstract Chordomas are rare tumors of the axial skeleton and skull base with few therapeutic options and no clinically validated molecular drug targets. The value of comprehensive genomic analyses for guiding medical therapy of patients with advanced-stage chordoma is unknown. We performed whole-exome and genome sequencing of tumor and matched germline control samples from 11 patients with locally advanced or metastatic chordoma within the MASTER program, a prospective clinical sequencing program of the German Cancer Consortium. All patients were pretreated and had progressive disease prior to molecular analysis. Genomic profiling showed that advanced chordomas are frequently characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair. First, DNA copy number profiles showed high numbers of structural variants greater than 10 million base pairs in size in the majority of cases. Second, all patients harbored somatic aberrations of at least 2 genes known to be involved in HR, and 10/11 cases harbored somatic alterations in 3 or more HR pathway genes. For example, 8 patients showed heterozygous BRCA2 deletions, which were associated with heterozygous deletions of ERCC6 in 6 patients and RAD54L in 7 patients, as well as PTEN alterations (heterozygous deletion, heterozygous mutation and deletion of the wildtype allele or loss of heterozygosity). Other recurrently altered HR genes included ATR, CHEK2, FANCC, FANCD2, FANCG, RAD18, RAD51B, and XRCC3. Third, pathogenic germline alterations were detected in 3 patients. A heterozygous BRCA2 frameshift mutation (p.T3085fs*26; ACMG Class 5), a heterozygous NBN frameshift mutation (p.K219Nfs*16; ACMG Class 5), and a heterozygous CHEK2 missense mutation (p.R145W; ACMG Class 4) were accompanied by somatic deletion of the respective wildtype alleles. Fourth, a mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and coincided with genomic instability. The high prevalence of an HR deficiency “footprint” in chordoma patients prompted us to explore the clinical efficacy of the poly(ADP-ribose) polymerase(PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells. Olaparib treatment of a patient whose tumor showed a prominent exposure to an HR deficiency-associated mutational signature, a high degree of genomic instability, and 13 heterozygous HR gene alterations halted tumor growth for 10 months. Whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain, providing novel insight into the mechanisms of PARP inhibitor resistance. In summary, our study has uncovered a key biological feature of advanced chordoma that represents an immediately actionable therapeutic target and provides a rationale for genomics-guided clinical trials of PARP inhibition in this intractable tumor entity. Citation Format: Stefan Gröschel, Daniel Hübschmann, Francesco Raimondi, Peter Horak, Gregor Warsow, Martina Fröhlich, Barbara Klink, Laura Gieldon, Barbara Hutter, Kortine Kleinhenz, David Bonekamp, Oliver Marschal, Priya Chudasama, Jagoda Mika, Marie Groth, Sebastian Uhrig, Stephen Krämer, Christoph Heining, Christoph Heilig, Daniela Richter, Eva Reisinger, Katrin Pfütze, Roland Eils, Stephan Wolf, Christof von Kalle, Christian Brandts, Claudia Scholl, Wilko Weichert, Stephan Richter, Sebastian Bauer, Roland Penzel, Evelin Schröck, Albrecht Stenzinger, Richard Schlenk, Benedikt Brors, Robert Russell, Hanno Glimm, Matthias Schlesner, Stefan Fröhling. Defective homologous recombination DNA repair as therapeutic target in advanced chordoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2723.

MTNR1B loss promotes chordoma recurrence by abrogating melatonin-mediated β-catenin signaling repression.

Chordoma is an extremely rare malignant bone tumor with a high rate of relapse. While cancer stem cells (CSCs) are closely associated with tumor recurrence, which depend on its capacity to self-renew and induce chemo-/radioresistance, whether and how CSCs participate in chordoma recurrence remains unclear. The current study found that tumor cells in recurrent chordoma displayed more dedifferentiated CSC-like properties than those in corresponding primary tumor tissues. Meanwhile, MTNR1B deletion along with melatonin receptor 1B (MTNR1B) down-regulation was observed in recurrent chordoma. Further investigation revealed that activation of Gαi2 by MTNR1B upon melatonin stimulation could inhibit SRC kinase activity via recruiting CSK and SRC, increasing SRC Y530 phosphorylation, and decreasing SRC Y419 phosphorylation. This subsequently suppressed β-catenin signaling and stemness via decreasing β-catenin p-Y86/Y333/Y654. However, MTNR1B loss in chordoma mediated increased CSC properties, chemoresistance, and tumor progression by releasing melatonin's repression of β-catenin signaling. Clinically, MTNR1B deletion was found to correlate with patients' survival. Together, our study establishes a novel convergence between melatonin and β-catenin signaling pathways and reveals the significance of this cross talk in chordoma recurrence. Besides, we propose that MTNR1B is a potential biomarker for prediction of chordoma prognosis and selection of treatment options, and chordoma patients might benefit from targeting MTNR1B/Gαi2/SRC/β-catenin axis.