Quality of life in chordoma survivors: results from the Chordoma Foundation Survivorship Survey.

OBJECTIVE: Chordomas are rare malignant bone tumors whose location in the skull base or spine, invasive surgical treatment, and accompanying adjuvant radiotherapy may all lead patients to experience poor quality of life (QOL). Limited research has been conducted on specific demographic and clinical factors associated with decreased QOL in chordoma survivors. Thus, the aim of the present study was to investigate several potential variables and their impact on specific QOL domains in these patients as well the frequencies of specific QOL challenges within these domains. METHODS: The Chordoma Foundation (CF) Survivorship Survey was electronically distributed to chordoma survivors subscribed to the CF Chordoma Connections forum. Survey questions assessed QOL in three domains: physical, emotional/cognitive, and social. The degree of impairment was assessed by grouping the participants into high- and low-challenge groups designated by having ≥ 5 or < 5 symptoms or challenges within a given QOL domain. Bivariate analysis of demographic and clinical characteristics between these groups was conducted using Fisher's exact test and the Mann-Whitney U-test. RESULTS: A total of 665 chordoma survivors at least partially completed the survey. On bivariate analysis, female sex was significantly associated with increased odds of significant emotional (p = 0.001) and social (p = 0.019) QOL burden. Younger survivors (age < 65 years) were significantly more likely to experience significant physical (p < 0.0001), emotional (p < 0.0001), and social (p < 0.0001) QOL burden. Skull base chordoma survivors had significantly higher emotional/cognitive QOL burden than spinal chordoma survivors (p = 0.022), while the converse was true for social QOL challenges (p = 0.0048). Survivors currently in treatment were significantly more likely to experience significant physical QOL challenges compared with survivors who completed their treatment > 10 years ago (p = 0.0074). Fear of cancer recurrence (FCR) was the most commonly reported emotional/cognitive QOL challenge (49.6%). Only 41% of the participants reported having their needs met for their physical QOL challenges as well as 25% for emotional/cognitive and 18% for social. CONCLUSIONS: The authors' findings suggest that younger survivors, female survivors, and survivors currently undergoing treatment for chordoma are at high risk for adverse QOL outcomes. Additionally, although nearly half of the participants reported a FCR, very few reported having adequate emotional/cognitive care. These findings may be useful in identifying specific groups of chordoma survivors vulnerable to QOL challenges and bring to light the need to expand care to meet the QOL needs for these patients.

The NIH pediatric/young adult chordoma clinic and natural history study: Making advances in a very rare tumor.

BACKGROUND: Chordomas are rare tumors arising from the skull base and spine, with approximately 20 pediatric chordoma cases in the Unitedn States per year. The natural history and optimal treatment of pediatric chordomas, especially poorly differentiated and dedifferentiated subtypes, is incompletely understood. Herein, we present findings from our first National Cancer Institute (NCI) chordoma clinic and a retrospective analysis of published cases of pediatric poorly differentiated chordomas (PDC) and dedifferentiated chordomas (DC). METHODS: Patients less than 40 years old with chordoma were enrolled on the NCI Natural History and Biospecimens Acquisitions Study for Children and Adults with Rare Solid Tumors protocol (NCT03739827). Chordoma experts reviewed patient records, evaluated patients, and provided treatment recommendations. Patient-reported outcomes, biospecimens, and volumetric tumor analyses were collected. A literature review for pediatric PDC and DC was conducted. RESULTS: Twelve patients (median age: 14 years) attended the clinic, including four patients with active disease and three patients with PDC responsive to systemic therapy. Consensus treatment, management, and recommendations were provided to patients. Literature review returned 45 pediatric cases of PDC or DC with variable treatments and outcomes. CONCLUSIONS: A multidisciplinary expert clinic was feasible and successful in improving understanding of pediatric chordoma. While multimodal approaches have all been employed, treatment for PDC has been inconsistent and a recommended standardized treatment approach has not been defined. Centralized efforts, inclusive of specialized chordoma-focused clinics, natural history studies, and prospective analyses will help in the standardization of care for this challenging disease.

Quality of Life in Chordoma Co-Survivors: Results from the Chordoma Foundation Survivorship Survey.

BACKGROUND: Chordomas are a rare form of aggressive bone cancer and are associated with poor quality of life (QOL). The present study sought to characterize demographic and clinical characteristics associated with QOL in chordoma co-survivors (caregivers of patients with chordoma) and assess whether co-survivors access care for QOL challenges. METHODS: The Chordoma Foundation Survivorship Survey was electronically distributed to chordoma co-survivors. Survey questions assessed emotional/cognitive and social QOL, with significant QOL challenges being defined as experiencing ≥5 challenges within either of these domains. The Fisher exact test and Mann-Whitney U test were used to analyze bivariate associations between patient/caretaker characteristics and QOL challenges. RESULTS: Among the 229 respondents to our survey, nearly half (48.5%) reported a high number (≥5) of emotional/cognitive QOL challenges. Co-survivors younger than 65 years were significantly more likely to experience a high number of emotional/cognitive QOL challenges (P < 0.0001), whereas co-survivors >10 years past the end of treatment were significantly less likely to experience a high number of emotional/cognitive QOL challenges (P = 0.012). When asked about access to resources, a lack of knowledge of resources to address their emotional/cognitive and social QOL issues (34% and 35%, respectively) was the most common response. CONCLUSIONS: Our findings suggest that younger co-survivors are at high risk for adverse emotional QOL outcomes. In addition, more than one third of co-survivors did not know about resources to address their QOL issues. Our study may help guide organizational efforts to provide care and support to patients with chordoma and their loved ones.

Radiotherapy After Gross Total Resection of Skull Base Chordoma: A Surveillance, Epidemiology, and End Results Database Analysis of Survival Outcomes.

OBJECTIVE: Skull base chordoma is a rare and locally destructive malignancy which presents unique therapeutic challenges. While achieving gross total resection (GTR) confers the greatest survival advantage, the role of adjuvant radiotherapy (RT) for patients who receive GTR remains unclear in the absence of prospective trials. Here, we aim to assess the effect of RT on survival outcomes in skull base chordoma patients who receive GTR by utilizing the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Patients with diagnostic, primary site, and resection codes specific for chordoma, skull base, and GTR, respectively, were queried in the SEER database (2000-2018). Kaplan-Meier curves (log-rank test) were constructed and Cox proportional hazards models were used to assess survival outcomes. RESULTS: A total of 115 skull base chordomas undergoing GTR were identified, of which 37 (32%) received no RT and 78 (68%) received RT. Median follow-up was 55.00 months (range: 0.00-227.00). Overall survival (OS) of patients with GTR was 85% and 70% at 5 and 10 years, respectively. Multivariate Cox proportional hazard analysis among chordoma patients undergoing GTR found age ≥65 (P < 0.01) was associated with poorer OS outcomes. RT appeared to trend toward offering benefit in terms of OS in patients after GTR, however this did not achieve statistical significance in the adjusted model (HR = 0.51, CI = 0.23-1.16, P = 0.09). When comparing, disease-specific survival was also not improved in patients undergoing RT (HR = 0.58, CI = 0.23-1.46, P = 0.25). CONCLUSIONS: It remains unclear whether RT after GTR of chordoma improved survival outcomes among SEER database patients.

Connexin43 confers Temozolomide resistance in human glioma cells by modulating the mitochondrial apoptosis pathway.

Glioblastoma multiforme (GBM) is the most aggressive astrocytoma, and therapeutic options are generally limited to surgical resection, radiotherapy, and Temozolomide (TMZ) chemotherapy. TMZ is a DNA alkylating agent that causes DNA damage and induces cell death. Unfortunately, glioma cells often develop resistance to TMZ treatment, with DNA de-methylation of the MGMT promoter identified as the primary reason. However, the contributions from proteins that normally protect cells against cytotoxic stress in TMZ-induced apoptosis have not been extensively explored. Here, we showed that increasing the level of the gap junction protein, Cx43, in human LN18 and LN229 glioma cells enhances resistance to TMZ treatment while knockdown of Cx43 in these same cells sensitizes them to TMZ treatment. By expressing a channel-dead or a C-terminal truncation mutant of Cx43, we show that Cx43-mediated TMZ resistance involves both channel dependent and independent functions. Expression of Cx43 in LN229 cells decreases TMZ-induced apoptosis, as determined by Annexin V staining. Cx43-mediated chemoresistance appears to be acting via a mitochondrial apoptosis pathway as manifested by the reduction in Bax/Bcl-2 ratio and the release of cytochrome C. Our findings highlight additional mechanisms and proteins that contribute to TMZ resistance, and raise the possibility of increasing TMZ efficiency by targeting Cx43 protein. This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap Junction Channels and Hemichannels'.