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OBJECTIVEChordoma is a slow-growing, locally aggressive cancer that is minimally responsive to conventional chemotherapy and radiotherapy and has high local recurrence rates after resection. Currently, there are no rodent models of spinal chordoma. In the present study, the authors sought to develop and characterize an orthotopic model of human chordoma in an immunocompromised rat.METHODSThirty-four immunocompromised rats were randomly allocated to 4 study groups; 22 of the 34 rats were engrafted in the lumbar spine with human chordoma. The groups were as follows: UCH1 tumor–engrafted (n = 11), JHC7 tumor–engrafted (n = 11), sham surgery (n = 6), and intact control (n = 6) rats. Neurological impairment of rats due to tumor growth was evaluated using open field and locomotion gait analysis; pain response was evaluated using mechanical or thermal paw stimulation. Cone beam CT (CBCT), MRI, and nanoScan PET/CT were performed to evaluate bony changes due to tumor growth. On Day 550, rats were killed and spines were processed for H & E–based histological examination and immunohistochemistry for brachyury, S100β, and cytokeratin.RESULTSThe spine tumors displayed typical chordoma morphology, that is, physaliferous cells filled with vacuolated cytoplasm of mucoid matrix. Brachyury immunoreactivity was confirmed by immunostaining, in which samples from tumor-engrafted rats showed a strong nuclear signal. Sclerotic lesions in the vertebral body of rats in the UCH1 and JHC7 groups were observed on CBCT. Tumor growth was confirmed using contrast-enhanced MRI. In UCH1 rats, large tumors were observed growing from the vertebral body. JHC7 chordoma–engrafted rats showed smaller tumors confined to the bone periphery compared with UCH1 chordoma–engrafted rats. Locomotion analysis showed a disruption in the normal gait pattern, with an increase in the step length and duration of the gait in tumor-engrafted rats. The distance traveled and the speed of rats in the open field test was significantly reduced in the UCH1 and JHC7 tumor–engrafted rats compared with controls. Nociceptive response to a mechanical stimulus showed a significant (p < 0.001) increase in the paw withdrawal threshold (mechanical hypalgesia). In contrast, the paw withdrawal response to a thermal stimulus decreased significantly (p < 0.05) in tumor-engrafted rats.CONCLUSIONSThe authors developed an orthotopic human chordoma model in rats. Rats were followed for 550 days using imaging techniques, including MRI, CBCT, and nanoScan PET/CT, to evaluate lesion progression and bony integrity. Nociceptive evaluations and locomotion analysis were performed during follow-up. This model reproduces cardinal signs, such as locomotor and sensory deficits, similar to those observed clinically in human patients. To the authors’ knowledge, this is the first spine rodent model of human chordoma. Its use and further study will be essential for pathophysiology research and the development of new therapeutic strategies.

Abstract Background Biliary tract malignancies, in particular cholangiocarcinomas (CCA), are rare tumors that carry a poor prognosis. BRCA2 mutation carriers have an increased risk of developing CCA with a reported relative risk of ∼5 according to the Breast Cancer Linkage Consortium. In addition to this risk, there are potential therapeutic implications in those harboring somatic and/or germline (GL) BRCA mutations. Therefore, it is important to define the clinical characteristics of GL/somatic BRCA1/2 variants in CCA patients. Materials and Methods We performed a multicenter retrospective analysis of CCA patients diagnosed between January 2000 and December 2013 with GL or somatic variants in BRCA1/2 genes detected by GL mutations testing and/or by tumor next generation sequencing. Cases were identified from clinical databases at participating institutions. Data including demographics, clinical history, surgical procedures, and systemic chemotherapy or radiation were extracted from patients' records. Results Overall, 18 cases were identified: 5 carriers of GL BRCA1/2 mutations (4 BRCA2; 1 BRCA1) and 13 harboring somatic variations (7 BRCA1; 6 BRCA2). Mean age at diagnosis was 60, SD ± 10 years (range 36–75 years), with male and female prevalence rates of 61.2% and 38.8%, respectively. Stage at diagnosis was I (n = 4), II (n = 3), III (n = 3), and IV (n = 8). Six patients had extrahepatic CCA and the rest intrahepatic CCA. Thirteen patients received platinum-based therapy and four were treated with poly ADP ribose polymerase inhibitors, of whom one experienced sustained disease response with a progression-free survival of 42.6 months. Median overall survival from diagnosis for patients with stage I/II in this study was 40.3 months (95% confidence interval [CI], 6.73–108.15) and with stages III/IV was 25 months (95% CI, 15.23–40.57). Conclusion BRCA-associated CCA is uncommon. This multicenter retrospective study provides a thorough clinical analysis of a BRCA-associated CCA cohort, which can serve as a benchmark for future development and design of expanded analyses and clinical trials.

Abstract Aims Chronic kidney disease (CKD) is prevalent and is associated with increased cardiovascular morbidity and mortality. The interaction between diastolic dysfunction (DD) and CKD in subjects with preserved systolic function is not well defined. This study sought to determine the association between renal function and DD in subjects with preserved ejection fraction. Methods and results Through the Rochester Epidemiology Project, subjects who underwent echocardiography over 2 years with EF ≥50% were identified and the clinical data were obtained. Glomerular filtration rate (GFR) was estimated using the modification of diet in renal disease equation. Linear regression was used to test for association of GFR and DD. DD was defined as follows: Grade 2 or pseudonormal pattern (0.75 &lt; E/A ≤ 1.5, E/e′ ≥ 10, DT &gt; 140 ms, ΔE/A ≥ 0.5, and PV S &lt; D) or Grade 3+ or restrictive pattern (E/A &gt; 1.5, E/e′ ≥ 10, DT &lt; 140 ms, and PV S &lt; D). Cox regression was used to assess correlation of GFR and DD with time-to-event outcomes. A total of 2056 patients were identified. There was significant correlation between worsening GFR and degree of DD assessed by echo Doppler E/e′ ratio (P = 0.005), left ventricular mass index (P = 0.004), and right ventricular systolic pressure (P = 0.01). Worsening GFR was associated with increased mortality, development of heart failure, and hospitalization (P &lt; 0.001). Within each GFR group, abnormal DD was associated with a higher risk of the clinical outcomes. No interaction between GFR and DD was noted, suggesting an increased risk of events associated with abnormal DD across ranges of GFR. Conclusions Worsening GFR was associated with a greater degree of diastolic dysfunction and adverse clinical outcomes. Within each GFR group, the presence of DD was associated with increased morbidity and mortality. Further studies are warranted to determine if improving DD in patients with CKD will benefit clinical outcomes.

Abstract In 2001, The American Association of Immunologists Committee on the Status of Women conducted a survey examining the percentage of women faculty members within immunology departments or women in immunology graduate programs across 27 institutions in the United States, comparing it to the percentage of women receiving a Ph.D. Here, we examine the representation of women across these same 27 immunology departments and programs to examine changes in gender equity over the last 15 years.

BACKGROUNDBiliary tract cancers (BTCs) are uncommon and are associated with a dismal prognosis. Combinations of gemcitabine and platinum chemotherapy (gemcitabine and platinum–based therapy [GP]) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for a GP response in BTC, this study evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance.METHODSPretreatment, formalin‐fixed, paraffin‐embedded samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression‐free survival (PFS), and overall survival (OS).RESULTSWhen genes with an incidence > 10% were considered, no individual gene was independently predictive of a GP response. In patients with unresectable BTC who received GP as their first‐line therapy, the joint status of cyclin‐dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and AT‐rich interaction domain 1A (ARID1A) was associated with PFS (P = .0004) and OS (P ≤ .0001). Patients with mutations in CDKN2A and TP53 were identified as a poor‐prognosis cohort with a median PFS of 2.63 months and a median OS of 5.22 months. Patients with mutant ARID1A, regardless of the single‐mutation status of TP53 or CDKN2A, had similar outcomes. A patient who exhibited mutations in all 3 genes had a median PFS of 20.37 months, and OS was not reached.CONCLUSIONSIn the largest exploratory analysis of this kind for BTC, 3 prevalent, mutually exclusive mutations represent distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker for a GP response. Prospective studies to validate these findings are needed, and they should include the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC. Cancer 2016;122:3657‐66. © 2016 American Cancer Society.

We present a case of a 17-year-old football player who had previously received multiple facet joint injections for presumed secondary osteoarthritis. 99 mTc-methylene diphosphonate single-photon emission computed tomography/computed tomography imaging of the cervical spine demonstrated focal increased radiopharmaceutical activity in the right C2 lamina, which was associated with an osteolytic lesion with a central irregular sclerotic nidus. Surgical pathology confirmed an osteoid osteoma.