Clinical-proteomic classification and precision treatment strategy of chordoma.

Chordoma is a rare and heterogeneous mesenchymal malignancy, with distinct clinical and biological behaviors. Till now, its comprehensive clinical-molecular characteristics and accurate molecular classification remain obscure. In this research, we enroll 102 patients with chordoma and describe their clinical, imageological, and histopathological features. Through tandem mass tag-based proteomic analysis and nonnegative matrix factorization clustering, we classify chordoma into three molecular subtypes: bone microenvironment-dominant, mesenchymal-derived, and mesenchymal-to-epithelial transition-mediated pattern. The three subtypes exhibit discrete clinical prognosis and distinct biological attributes of osteoclastogenesis and immunogenicity, oxidative phosphorylation, and receptor tyrosine kinase activation, suggesting targeted therapeutic strategies of denosumab, S-Gboxin, and anlotinib, respectively. Notably, these approaches demonstrate positive treatment outcomes for each subtype in vitro and in vivo. Altogether, this work sheds light on the clinical-proteomic characteristics of chordoma and provides a candidate precision treatment strategy for chordoma according to molecular classification, underscoring their potential for clinical application.

Tailored surgical approaches for spinal chordomas: A multidisciplinary perspective.

INTRODUCTION: The treatment of spinal chordomas presents a significant challenge due to their resistance to both radiotherapy and chemotherapy as well as the complexity of the surgical procedures required. This study presents a series of cases of primary spinal chordomas, focusing on the development of a personalized therapeutic strategy that is tailored to each patient's unique clinical status. This approach aims to ensure that treatments are optimally aligned with the patient's overall prognosis and surgical eligibility. METHODS: This retrospective study analyzed 14 patients with primary spinal chordomas treated at our institution. We evaluated surgical strategies, clinical outcomes, and survival rates, The therapeutic strategy was formulated after interdisciplinary conferences with sarcoma management specialists. Data were collected on patient demographics, surgical details, postoperative outcomes, and follow-up status. RESULTS: All patients presented with neurological deficits preoperatively, which generally improved post-surgery. The study included a detailed analysis of two distinct surgical approaches: five patients underwent en bloc resection with dorsal stabilization and nine received decompression only. Patients undergoing en bloc resection showed a reduced need for additional surgery due to the comprehensive removal of the tumor. As anticipated, 40% of the patients who underwent decompression experienced tumor progression within the first three months. However, given the poor overall prognosis, the objective of maintaining neurological function was achieved. CONCLUSIONS: Surgical en bloc resection offers a viable and effective intervention for spinal chordomas, enhancing neurological function. It is imperative to tailor treatment strategies to individual prognoses, integrating insights from multidisciplinary discussions that meticulously evaluate surgical risks. This collaborative approach aids in selecting the most appropriate surgical technique tailored to each patient's specific condition.

Spinal chordoma and chondrosarcoma treatment experiences - a 20-year retrospective study from databases of two medical centers.

The research retrospectively analyzed cases of spinal chordoma and chondrosarcoma involving patients who received treatment at the two hospitals between 2001 and 2023. Among the 48 patients studied (39 chordoma and 9 chondrosarcoma cases), the average age was 53.9 ± 15.8 years, with a range of 17 to 86 years. Out of these patients, 43 underwent excision surgery and were categorized based on tumor margin into negative (R0) or microscopically positive (R1) margin (n = 14) and macroscopically positive (R2) margin (n = 29) groups. The mean overall survival (OS) for R0/R1 and R2 groups was 156.5 ± 19.3 and 79.2 ± 11.9 months, respectively (p value = 0.012). The mean progression-free survival (PFS) for R0/R1 and R2 was 112.9 ± 24.4 and 25.5 ± 5.5 months (p value < 0.001). The study showed that regardless of whether patients in the R0/R1 or R2 groups received radiation therapy (RT) or not, there was no significant improvement in OS or PFS. Specifically, the OS and PFS for the RT only group were 75.9 ± 16.6 and 73.3 ± 18.0 months. In conclusion, the recommended treatment approach for spinal chordoma and chondrosarcoma remains en bloc resection surgery with an appropriate margin. Patients who are unsuitable for or decline surgery may find a beneficial disease control rate with traditional external beam photon/proton therapy.

Role of Proton Beam Therapy in Spinal Chordomas: A Narrative Review of The Literature.

Chordomas are rare malignant neoplasms arising from vestigial remnants of the embryonic notochord. Approximately 55-70% of chordomas develop within the vertebral column. Their affinity to develop within the bones of the axial skeleton and propensity to locally invade and recur makes them challenging candidates for complete surgical excision. Adjuvant therapies are hence necessary to improve outcomes; for which chemotherapy has been observed to be largely ineffective, owing to the tumour being resistant to it. Radiotherapy is the current adjuvant therapy of choice for chordoma management. Over the years, proton beam therapy (PBT) has been the subject of medical attention, given the dosimetric benefits it confers over traditional radiotherapy, allowing more concentrated radiation to be given to the target of interest and reducing damage to surrounding normal tissue. A review of the current literature reveals PBT offers significantly better outcomes when used as an adjuvant to maximal surgical resection rather than as a definitive therapy.

Comparative overall survival analysis of chordomas of the base of the skull from the Surveillance, Epidemiology, and End Results (SEER) program between 2000 and 2020.

Chordomas of the skull base are rare, slow growing, locally invasive cancers with limited long-term survival analysis reported in the literature. We seek to provide comparative survival analysis of patients on a long-term (20-year) basis using population-level data. The Surveillance, Epidemiology, and End Results (SEER) program was queried for cases of chordoma relegated to the base of the skull, diagnosed between 2000 and 2020. Demographic, disease, and treatment information were analyzed using Cox proportional hazards and log-rank comparisons. 630 patients with chordoma of the skull base were identified. Age ≤ 49 years at diagnosis was associated with increased five-, 10-, and 20-year overall survival (hazard ratio (HR) = 0.39, 0.33, and 0.30, respectively; p < 0.001 for all). Treatment with surgery and adjuvant radiotherapy was associated with increased five-, 10-, and 20-year survival (HR = 0.71, 0.79, and 0.79, respectively; p < 0.001 for all). On univariate analysis, widowed patients had decreased survival (20-year overall survival = 34.8% [15.3%-34.8%] compared to married patients (74.4% [68.1%-80.8%]. Surgery remains the primary treatment associated with increased survival among patients with chordoma of the skull base, with adjuvant radiotherapy serving a complimentary role. Demographic factors such as marital status are also associated with changes in survival.

Skull Base Chordoma and Chondrosarcoma: Neuroradiologist's Guide to Diagnosis, Surgical Management, and Proton Beam Therapy.

Skull base chordomas and chondrosarcomas are distinct types of rare, locally aggressive mesenchymal tumors that share key principles of imaging investigation and multidisciplinary care. Maximal safe surgical resection is the treatment choice for each, often via an expanded endoscopic endonasal approach, with or without multilayer skull base repair. Postoperative adjuvant radiation therapy is frequently administered, usually with particle therapy such as proton beam therapy (PBT). Compared with photon therapy, PBT enables dose escalation while limiting damage to dose-limiting neurologic structures, particularly the brainstem and optic apparatus, due to energy deposition being delivered at a high maximum with a rapid decrease at the end of the penetration range (Bragg peak phenomenon). Essential requirements for PBT following gross total or maximal safe resection are tissue diagnosis, minimal residual tumor after resection, and adequate clearance from PBT dose-limiting structures. The radiologist should understand surgical approaches and surgical techniques, including multilayer skull base repair, and be aware of evolution of postsurgical imaging appearances over time. Accurate radiologic review of all relevant preoperative imaging examinations and of intraoperative and postoperative MRI examinations plays a key role in management. The radiology report should reflect what the skull base surgeon and radiation oncologist need to know, including distance between the tumor and PBT dose-limiting structures, tumor sites that may be difficult to access via the endoscopic endonasal route, the relationship between intradural tumor and neurovascular structures, and tumor sites with implications for postresection stability. ©RSNA, 2024 Supplemental material is available for this article.

Proteogenomic characterization of skull-base chordoma.

Skull-base chordoma is a rare, aggressive bone cancer with a high recurrence rate. Despite advances in genomic studies, its molecular characteristics and effective therapies remain unknown. Here, we conduct integrative genomics, transcriptomics, proteomics, and phosphoproteomics analyses of 187 skull-base chordoma tumors. In our study, chromosome instability is identified as a prognostic predictor and potential therapeutic target. Multi-omics data reveals downstream effects of chromosome instability, with RPRD1B as a putative target for radiotherapy-resistant patients. Chromosome 1q gain, associated with chromosome instability and upregulated mitochondrial functions, lead to poorer clinical outcomes. Immune subtyping identify an immune cold subtype linked to chromosome 9p/10q loss and immune evasion. Proteomics-based classification reveals subtypes (P-II and P-III) with high chromosome instability and immune cold features, with P-II tumors showing increased invasiveness. These findings, confirmed in 17 paired samples, provide insights into the biology and treatment of skull-base chordoma.

Clival chordomas and chondrosarcomas in Denmark-Outcomes in 33 patients following the national centralization of treatment in 2010.

PURPOSE: This 13-year consecutive case series aims to provide a comprehensive overview of all patients operated for clival chordomas and clival chondrosarcomas in Denmark since the centralization of treatment in 2010, comparing outcomes to international series. METHODS: This was a retrospective review of 33 patients with clival tumors, comprising 22 chordomas and 11 chondrosarcomas, who were treated at Copenhagen University Hospital between years 2010 and 2023. Data were collected from digital patient records and pathology reports. RESULTS: The symptoms leading to diagnosis primarily included double vision, headaches, and dizziness. In general, patients were in good health, with a mean Charlson Comorbidity Index score of 1.6. The complication rate of the index surgery was 51.5%. Adjuvant radiotherapy was applied in 51.5% of the cases. In patients with clival chordomas, the mean age was 51.1 years, ranging from 16 to 83 years. At the time of diagnosis, the mean tumor volume was 20.9 cm3 and the five-year overall survival rates were 79.1% (95% confidence interval (CI): 62.4-100). In patients with chondrosarcomas, the mean age was 48.2 years, ranging from 15 to 76 years. At the time of diagnosis, the mean tumor volume was 22.3 cm3 and the five-year overall survival 90% (95% CI: 73.2-100). CONCLUSION: The centralized treatment of clival tumors in Denmark demonstrates incidence, survival, and complication rates comparable to those found in other international series. Given the variations in treatment strategies, tumor localizations across series, and small sample sizes, the further analysis of larger compiled multicenter datasets for clival tumors could provide more solid evidence regarding the management of these rare tumors.

Interleukin-7 expression by CAR-T cells improves CAR-T cell survival and efficacy in chordoma.

Chordoma is a rare bone tumor that frequently recurs after surgery, and the prognosis is poor with current treatments. This study aimed to identify potential novel immunotherapeutic targets for chordomas by identifying target proteins in clinical samples as well as tumor microenvironmental factors to enhance efficacy. Fourteen chordoma samples were analyzed by single-cell RNA sequencing, and B7-H3 and IL-7 were identified as potential targets and potentiators, respectively. B7-H3-targeted chimeric antigen receptor T (CAR-T) cells and B7-H3 CAR-T cells expressing IL-7 were synthesized and their anti-tumor activity evaluated in vitro, including in primary chordoma organoid models. The B7-H3 CAR-T/IL-7 therapy showed enhanced cytotoxicity and prolonged duration of action against tumor cells. Additionally, IL-7 modulated favorable subpopulations of cultured CAR-T cells, diminished immune checkpoint expression on T-cell surfaces, and enhanced T-cell functionality. The incorporation of IL-7 molecules into the B7-H3 CAR structure augmented CAR-T-cell function and improved CAR-T-cell efficacy, thus providing a novel dual therapeutic strategy for chordoma treatment.

Coccygeal tumours unveiled: a retrospective cohort analysis from a tertiary referral centre.

BACKGROUND: Isolated tumours affecting the coccyx are infrequent, with only a handful of documented cases in the literature. Herein, we highlight the most extensive consecutive case series involving various isolated coccyx tumours with varied clinical presentations and imaging features. METHODS: A retrospective search of our tertiary Orthopaedic oncology institute's oncology and Radiology database [Radiology Information System, Picture Archiving and Communication System, and Computerised Radiology Information System] for the keyword "Coccyx" and "Tumour" was performed over 15 years (between December 2007 and August 2022). Data collected was correlated with local histopathology and laboratory records. Patient demographics, clinical characteristics, and complementary imaging findings were recorded for analysis. RESULTS: One hundred and three lesions originating in the coccyx with a mean age of 62 years (range 25-90 years) were identified. There was a male preponderance with 59 male and 44 female patients (1.3:1.0). The most typical tumour noted was chordoma. Other lesions included a dermoid cyst, a myxopapillary ependymoma, a notochordal remnant, an osteochondroma, an Ewing sarcoma, and a teratoma. CONCLUSION: Our analysis suggests that most of the tumours involving coccyx are chordomas with a few rarely encountered benign and malignant tumours. Radiological imaging plays a vital role in characterising isolated tumours affecting the coccyx and guiding appropriate patient management. ADVANCES IN KNOWLEDGE: This is the largest reported series of coccygeal tumours. Chordoma is the commonest coccygeal tumour. Patients with unexplained coccydynia should undergo detailed investigations, preferably with cross-sectional imaging.

Genomic profiles and clinical presentation of chordoma.

Chordoma is a rare bone cancer with variable clinical outcomes. Here, we recruited 184 sporadic chordoma patients from the US and Canada and collected their clinical and treatment data. The average age at diagnosis was 45.5 years (Range 5-78) and the chordoma site distribution was 49.2% clivus, 26.2% spinal, and 24.0% sacral. Most patients (97.5%) received surgery as the primary treatment, among whom 85.3% also received additional treatment. Except for the most prevalent cancers like prostate, lung, breast, and skin cancer, there was no discernible enrichment for any specific cancer type among patients or their family members. Among a subset of patients (N = 70) with tumor materials, we conducted omics analyses and obtained targeted panel sequencing and SNP array genotyping data for 51 and 49 patients, respectively. The most recurrent somatic driver mutations included PIK3CA (12%), followed by chromatin remodeling genes PBRM1 and SETD2. Amplification of the 6q27 region, containing the chordoma susceptibility gene TBXT, was detected in eight patients (16.3%). Clival patients appeared to be less likely to carry driver gene mutations, chromosome arm level deletion events (e.g., 5p, 5p, and 9p), or 6q27 amplification compared to sacral patients. After adjusting for age, sex, tumor site, and additional treatment, patients with somatic deletions of 14q (OR = 13.73, 95% CI 1.96-96.02, P = 0.008) and 18p (OR = 13.68, 95% CI 1.77-105.89, P = 0.012) were more likely to have persistent chordoma. The study highlights genomic heterogeneity in chordoma, potentially linked to location and clinical progression.

The impact of socioeconomic determinants on the access to care and survival in patients with spinal chordomas- a national cancer database analysis.

PURPOSE: Chordomas are rare malignant neoplasms primarily treated surgically. Disparities related to race and socioeconomic status, may affect patient outcomes. This study aims to identify prognostic factors for access to care and survival in patients with spinal chordomas. METHODS: The NCDB database was queried between the years 2004 and 2017. Kaplan-Meier curves were constructed to compare survival probabilities among different groups, based on race and socioeconomic determinents. RESULTS: 1769 patients were identified, with 87% being White, 5% Hispanic, 4% Black, and Asian each. The mean age was 61.3 years. Most patients received care at academic/research centers and lived in a large metropolitan area, with no difference between races. A significantly higher percentage of Black patients did not undergo surgery (p < 0.001), with no statistically significant difference in survival between races (p = 0.97). A higher survival probability was seen in patients with other government insurances (p < 0.0001), in higher income quartiles (p < 0.0001), in metropolitan areas (p = 0.023), and at an academic/research center (p < 0.0001). A lower survival probability was seen in patients who are uninsured, in rural areas, and at community cancer programs (p < 0.0001). CONCLUSION: This study highlights disparities in access to surgical intervention for patients with spinal chordomas, especially among Black individuals. It emphasizes the significant impact of insurance status and income on access to surgical care and highlights geographical and institutional variations in survival rates. Addressing socioeconomic differences is crucial for fostering equity in neurosurgical outcomes.

[Analysis of influencing factors of recurrence after en bloc spondylectomy of spinal tumors].

Objectives: To investigate the survival and tumor recurrence after en bloc spondylectomy of spinal tumor and analyze the risk factors of postoperative tumor recurrence. Methods: This is a retrospective case series study. Data of 101 patients undergoing en bloc spondylectomy of spinal tumors in the Musculoskeletal Tumor Center, Peking University People's Hospital from December 2006 to June 2022 were analyzed. There were 58 males and 43 females, aged (38.2±15.8) years (range: 10 to 79 years) at the time of surgery; the follow-up time was(44.0±36.0) months (range: 12 to 171 months).Among them, there were 25 relapsed patients, with 7 females and 18 males; aged (34.8±16.3) years (range: 12 to 66 years) at the time of surgery. The types of tumors included 5 giant cell tumors of bone, 6 osteosarcomas, 1 chordoma, 5 chondrosarcomas, 1 undifferentiated sarcoma, 1 fibrosarcoma, 2 Ewing sarcomas, 3 metastases and 1 malignant giant cell tumor of bone. Survival analysis of overall and relapsed patients were performed using the Kaplan-Meier curves. A segmented regression model was used to fit the sequence of recurrence rate changes over time since admission and identify change points for further analysis on risk factors. Univariate and multivariate Logistic regression analysis were performed to assess risk factors associated with recurrence rate; results from multivariate regression analysis were presented using a forest plot. Results: The tumor recurrence rate after en bloc spondylectomy was 24.8% (25/101).The overall median recurrence-free survival after en bloc spondylectomy was 161 months (95%CI: 92 months to NA).The median recurrence-free survival of recurrent patients was 13 months (95%CI: 12 to 27 months).Regarding the classification based on tumor malignancy, and relapse-free survival of metastatic tumors was significantly shorter (P=0.007); and among the surgical margin groups, relapse-free survival of R0 group was significantly better than the R1 and R2 groups (P<0.01). According to the segmented regression model, the tumor recurrence rate for en bloc spondylectomy showed a significant downward trend over time, with relatively higher recurrence rates before 2009 and a relatively stable trend after 2014. The results of univariate analysis showed that surgical margin and time of admission were the influencing factors of patient recurrence. The results of multivariate analysis showed that the R1 resection(OR=13.453,95%CI:2.897 to 97.941,P=0.002) and R2 resection(OR=11.379,95%CI:2.658 to 79.429,P=0.003) were independent influencing factor affecting patient recurrence. Conclusions: The overall tumor recurrence rate after en bloc spondylectomy was high. The surgical margin of tumor resection is an independent risk factor affecting tumor recurrence. Specifically, R2 and R1 resections significantly increase the risk of tumor recurrence.

Two-stage surgery for large sacrococcygeal chordomas: How I do it.

Sacrococcygeal chordoma is a malignant, slow-growing, and locally aggressive bone tumor. A wide surgical margin is recommended to prevent local recurrence and metastasis. This disease tends to cause massive defects when rectal resection and sacrectomy are required. Therefore, soft tissue reconstruction is required and a pedicled vertical rectus abdominis muscle flap (VRAM) is a viable option. Important anatomical landmarks, advantages and limitations are discussed and the procedure is described step by step. This case report presents a two-stage operation with an anterior rectal resection and VRAM flap harvest followed by a complementary posterior approach with sacrectomy and soft tissue reconstruction: approach and results. The wound completely healed in six weeks. Three years after surgery, no local recurrence or distal metastasis was detected. This two-stage strategy presents a viable and safe option for large sacrococcygeal chordomas.

Notochordal cell derived lesions: a 55-year casuistic analysis of 50 cases with radiologic-pathologic correlation in a tertiary referral hospital, and literature review.

Distinct lesions are derived from notochordal cells (NCDL), ranging from benign to malignant ones. This study presents fifty NCDL cases diagnosed in a tertiary hospital of reference from the past 55 years: forty-two conventional chordomas, including one chondroid chordoma subtype, four benign notochordal cell tumors (BNCT), two conventional chordomas with BNCT foci, and two dedifferentiated chordomas. All patients were adults. Three BNCT were incidentally diagnosed, and one case presented local pain. Chordomas began with local pain and/or neurological symptoms. BNCT were well-defined intraosseous lesions, hypointense on T1-weighted images (WI) and hyperintense on T2-WI, without enhancement in the contrast. Conventional chordomas, including its chondroid subtype, were lobulated masses with cortical disruption and soft tissue extension, hypointense on T1-WI and hyperintense on T2-WI, with variable contrast enhancement. BNCT were histologically composed of solid sheets of vacuolated cells with clear cytoplasm and round and central nuclei. No atypia, lobular growth pattern, myxoid matrix, or bone infiltration were seen. Conventional chordomas were histologically composed of physaliphorous cells in a myxoid stroma with lobulated and infiltrating growth patterns. Observational follow-up using radiological controls was decided on for the BNCT cases. None of these cases presented local recurrence or metastasis. En-bloc resection and adjuvant radiotherapy were selected for sacral and vertebral chordoma cases. Sixteen patients died due to tumor-related factors; twenty-eight presented local recurrence, and four developed distant metastases. New therapeutic options are being studied for chordoma cases. Clinical, radiological, and histopathological data are necessary to properly diagnose and follow up of NCDL.

Primary lung chordoma: a case report.

BACKGROUND: Chordoma, a rare malignant tumor arising from notochordal tissue, usually occurs along the spinal axis. Only a few published reports of primary lung chordomas exist. Herein, we present a case of primary lung chordoma and discuss important considerations for diagnosing rare chordomas. CASE PRESENTATION: We report a case of primary lung chordoma in a 39-year-old male with a history of testicular mixed germ-cell tumor of yolk sac and teratoma. Computed tomography revealed slow-growing solid lesions in the left lower lobe. We performed wedge resection for suspected germ-cell tumor lung metastasis. Histologically, large round or oval cells with eosinophilic cytoplasm were surrounded by large cells with granular, lightly eosinophilic cytoplasm. Tumor cells were physaliphorous. Immunohistochemistry was positive for brachyury, S-100 protein, epithelial membrane antigen, vimentin, and cytokeratin AE1/AE3, suggesting pulmonary chordoma. Re-examination of the testicular mixed germ-cell tumor revealed no notochordal elements. Although some areas were positive for brachyury staining, hematoxylin and eosin (HE) staining did not show morphological features typical of chordoma. Complementary fluorescence in situ hybridization (FISH) of the lung tumor confirmed the absence of isochromosome 12p and 12p amplification. Thus, a final diagnosis of primary lung chordoma was established. CONCLUSIONS: In patients with a history of testicular mixed germ cell tumors, comparison of histomorphology using HE and Brachyury staining of lung and testicular tumors, and analyzing isochromosome 12p and 12p amplification in lung tumors using FISH is pivotal for the diagnosis of rare lung chordomas.

A dosiomics approach to treatment outcome modeling in carbon ion radiotherapy for skull base chordomas.

PURPOSE: To investigate the role of dosiomics features extracted from physical dose (DPHYS), RBE-weighted dose (DRBE) and dose-averaged Linear Energy Transfer (LETd), to predict the risk of local recurrence (LR) in skull base chordoma (SBC) treated with Carbon Ion Radiotherapy (CIRT). Thus, define and evaluate dosiomics-driven tumor control probability (TCP) models. MATERIALS AND METHODS: 54 SBC patients were retrospectively selected for this study. A regularized Cox proportional hazard model (r-Cox) and Survival Support Vector Machine (s-SVM) were tuned within a repeated Cross Validation (CV) and patients were stratified in low/high risk of LR. Models' performance was evaluated through Harrell's concordance statistic (C-index), and survival was represented through Kaplan-Meier (KM) curves. A multivariable logistic regression was fit to the selected feature sets to generate a dosiomics-driven TCP model for each map. These were compared to a reference model built with clinical parameters in terms of f-score and accuracy. RESULTS: The LETd maps reached a test C-index of 0.750 and 0.786 with r-Cox and s-SVM, and significantly separated KM curves. DPHYS maps and clinical parameters showed promising CV outcomes with C-index above 0.8, despite a poorer performance on the test set and patients stratification. The LETd-based TCP showed a significatively higher f-score (0.67[0.52-0.70], median[IQR]) compared to the clinical model (0.4[0.32-0.63], p < 0.025), while DPHYS achieved a significatively higher accuracy (DPHYS: 0.73[0.65-0.79], Clinical: 0.6 [0.52-0.72]). CONCLUSION: This analysis supports the role of LETd as relevant source of prognostic factors for LR in SBC treated with CIRT. This is reflected in the TCP modeling, where LETd and DPHYS showed an improved performance with respect to clinical models.

Chordoma: Genetics and Contemporary Management.

Chordomas, arising from notochord remnants, are rare neoplasms with aggressive growth patterns despite their histologically low-grade nature. This review explores their embryological origins, molecular markers like brachyury, and genetic alterations driving pathogenesis. Diagnosis relies on advanced imaging and biopsy confirmation due to overlapping features with chondrosarcoma. The WHO classification distinguishes conventional, dedifferentiated, and poorly differentiated chordomas, each with distinct prognostic implications. Recent genomic analyses uncovered recurrent mutations in PI3K signaling pathways and chromatin remodeling genes, informing prognostic models. Surgery remains the cornerstone of treatment, though adjuvant radiation complements surgical resection. Although chordomas are generally considered refractory to medical therapy, emerging targeted molecular strategies show potential promise in ongoing trials. This review aims to provide a concise yet comprehensive overview of chordomas, guiding clinicians in diagnosis, treatment, and prognostication for improved patient outcomes.

Hypofractionated proton and carbon ion beam radiotherapy for sacrococcygeal chordoma (ISAC): An open label, randomized, stratified, phase II trial.

INTRODUCTION: Sacrococcygeal chordomas have high recurrence rates and are challenging to treat. METHODS: In this phase II prospective, randomized, stratified trial, the safety and feasibility of hypofractionated ion radiation therapy were investigated. The primary focus was monitored through the incidence of Grade 3-5 NCI-CTC-AE toxicity. Secondary endpoints included local progression-free (LPFS) and overall survival (OS). RESULTS: The study enrolled 82 patients with primary (87 %) and recurrent (13 %) inoperable or incompletely resected sacral chordomas from January 2013 to July 2022, divided equally into proton therapy (Arm A) and carbon ion beam therapy (Arm B) groups, each receiving a total dose of 64 Gy (RBE) in 16 fractions, 5-6 fractions per week. Overall 74 % of patients received no previous surgery and 66 % of tumors were confirmed by a brachyury staining. The mean and median Gross Tumor Volume at the time of treatment (GTV) was 407 ml and 185 ml, respectively. The median follow-up of the surviving patients was 44.7 months, and the 2-year and 4-year OS rates were 96 % and 81 %, respectively. Factors such as smaller GTV and younger age trended towards better OS. The LPFS after 2-year and 4-year was 84 % and 70 %, respectively. Male gender emerged as a significant predictor of LPFS. There was no significant difference between the treatment groups. We observed five grade 4 wound healing disorders (6 %). CONCLUSION: The initial response rates were promising; however local control was not sustained. More comparative research on fractionation schemes is essential to refine treatment approaches for inoperable sacral chordoma.

Fractionated radiotherapy after gross-total resection of spinal chordoma: a systematic review of survival outcomes using individualized patient data.

OBJECTIVE: Spinal chordoma treatment guidelines recommend resection. However, in patients in whom gross-total resection (GTR) is achieved, the benefits of radiation therapy (RT) are unclear. Therefore, the authors performed a systematic review to determine if RT is associated with postoperative progression-free survival (PFS) or overall survival (OS) after achieving GTR of spinal chordoma. METHODS: The PubMed database was searched for studies including individualized data of patients undergoing GTR with or without RT for spinal chordoma. Patients < 18 years of age or those who underwent stereotactic body RT were excluded. Qualitative assessment was performed using Newcastle-Ottawa Scale guidelines. Log-rank tests for time-to-event data and a Cox proportional-hazards model were generated for a multivariable statistical model. RESULTS: Complete data of 132 patients were retrieved, with 37 (28%) patients receiving adjuvant RT and 95 (72%) not receiving adjuvant RT. The mean follow-up was not statistically significantly different between those undergoing RT and not undergoing RT (54.02 months and 65.43 months, respectively). Patients were more likely not to undergo RT if their disease was located in the sacrum versus the mobile spine (p < 0.001). When controlling for age ≥ 65 years, male sex, disease location, and treatment year ≥ 2010, patients undergoing RT had similar PFS and OS when compared with those not undergoing RT on multivariable survival analysis (HR 0.935 [95% CI 0.703-2.340], p = 0.844 and HR 2.078 [95% CI 0.848-5.090], p = 0.110, respectively). However, age ≥ 65 years was associated with poorer OS in adjusted analyses (HR 2.761 [95% CI 1.185-6.432], p = 0.018) relative to patients < 65 years of age. CONCLUSIONS: After achieving GTR of spinal chordoma, the utility of RT on PFS and OS remains unclear. Age ≥ 65 years appears to be associated with OS in spinal chordoma patients. Additional multicenter prospective studies are needed to determine the utility of RT in this patient population.