Introduction: True North was a phase 3, randomized, double-blind (DB), placebo (PBO)-controlled trial conducted at 285 sites in 30 countries (NCT02435992). Treatment with once-daily ozanimod (an oral sphingosine 1-phosphate [S1P] receptor modulator selectively targeting S1P1 and S1P5) in patients (pts) with moderately-to-severely active ulcerative colitis (UC) showed significant improvements in primary and all key secondary endpoints. Here we report findings on the consistency of clinical and endoscopic endpoints in the global and North American population. Methods: In True North, pts received either DB treatment with ozanimod HCl 1 mg (equivalent to ozanimod 0.92 mg) or matching PBO, or open-label ozanimod 1 mg over a 10-week (wk) induction period. Pts with clinical response to ozanimod at wk 10 were re-randomized 1:1 to receive DB maintenance treatment with ozanimod 1 mg or PBO through wk 52. The primary endpoint was proportion of pts in clinical remission at wks 10 and 52; key secondary endpoints included clinical response and endoscopic improvement. The global population included 1012 pts who received at least 1 dose of study medication during induction, and 457 who received at least 1 dose of study medication during maintenance. Here, we examine results from pts in North American sites. Results: A total of 247 pts were enrolled in North America, of which 167 received DB ozanimod (n=107) or PBO (n=60) during induction. At baseline, 41.1% and 48.3% of pts in the ozanimod and PBO groups, respectively, had previously received a biologic treatment for UC. At wk 10, 15.9% and 3.3% of pts in the ozanimod and PBO groups, respectively, achieved clinical remission. In addition, greater proportions of pts achieved clinical response and endoscopic improvement with ozanimod at wk 10 (Table 1). During maintenance, 105 pts from North America were re-randomized to treatment with ozanimod (n=56) or PBO (n=49). At wk 52, 39.3% and 12.2% of pts in the ozanimod and PBO groups, respectively, achieved clinical remission, and greater proportions of pts achieved clinical response and endoscopic improvement with ozanimod (Table 1). These outcomes from the North American population are consistent with those previously reported from the global population. Conclusion: In this post-hoc analysis, consistent with the global population, ozanimod treatment for up to 52 wks in North American pts with moderately-to-severely active UC showed benefits on clinical and endoscopic endpoints.Table 1.: Efficacy Outcomes from the North American Participants in True North.
A randomized study compared the Novak and Pipelle endometrial biopsy instruments with respect to quality of the biopsy obtained and pain related to the procedure. Fifty-five subjects were randomized to one of two groups. Twenty-six women had a biopsy using the Pipelle, followed immediately by one using the Novak instrument; 29 had the procedures performed in the reverse sequence. After the procedures, each woman completed a pain questionnaire. Individual histology slides were reviewed in a blinded fashion. The two biopsies from each subject were paired, and a reviewer indicated the preferred type of biopsy. The scores were analyzed by nonparametric tests. The instruments yielded biopsies of similar quality (z = -0.18, P = .856). Pain scores were lower for the Pipelle (z = -3.40, P = .001). The pathologist showed no preference when choosing Novak or Pipelle slides (chi 2 = 2.08, P = .149). In our patient population, the Pipelle instrument was comparable to the Novak instrument in obtaining adequate tissue and was significantly less painful.
Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, demonstrated superior efficacy and safety vs placebo for up to 52 weeks in adults with moderately to severely active ulcerative colitis (UC) in a phase 3 study (True North). In this post-hoc analysis, we evaluated the impact of prior biologic exposure on response to ozanimod.True North consisted of two cohorts. In cohort 1, patients with UC received double-blind treatment with once-daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo. In cohort 2, patients received open-label once daily ozanimod 0.92 mg. Ozanimod responders after a 10-week induction were re-randomized to double-blind maintenance with ozanimod 0.92 mg or placebo through week 52. Outcomes based on prior biologic exposure (biologic-naïve, 1 biologic, and 2+ biologics) and prior biologic type (anti-tumor necrosis factor [TNF] agents, vedolizumab, or both) were analyzed for clinical remission, clinical response, endoscopic improvement, and mucosal healing. Patients exposed to only a JAK inhibitor were excluded from the analysis.A total of 992 patients (n = 213 placebo and n = 426 ozanimod in cohort 1, n = 353 ozanimod in cohort 2) were included in the analysis for induction; 616 were biologic-naïve, 162 had exposure to 1 biologic, and 214 were exposed to 2 or more biologics. At baseline, biologic-exposed patients had more prior corticosteroid use, longer disease duration, and more extensive disease than biologic-naïve patients. During induction, greater therapeutic effects of ozanimod were generally seen in biologic-naïve vs biologic-exposed patients, and ozanimod-treated patients had greater responses on nearly all reported endpoints at week 10 (cohort 1). Clinical remission was achieved in 23% vs 6.6% of patients on ozanimod vs placebo who were biologic naïve, 17.2% vs 8.3% on 1 prior biologic, and 3.7% vs 2.5% on 2 or more biologics. Clinical response was reached in 53% vs 28% of patients on ozanimod vs placebo who were biologic naïve, 50% vs 33% on 1 biologic, and 27% vs 15% on 2 or more biologics. During maintenance, ozanimod-treated patients had greater responses on all endpoints versus placebo, with similar proportions of patients achieving clinical response to ozanimod regardless of prior biologic exposure (61% for biologic naïve, 60% for 1 biologic, and 55% for 2 or more biologics). At week 52, the proportion of patients on ozanimod with clinical remission was similar in the 1-biologic and 2+-biologic exposure groups (28% and 26%, respectively), and proportions of patients on ozanimod with endoscopic improvement and mucosal healing were similar for the 1-biologic and biologic-naïve groups (47% and 50%, 30%, and 33%, respectively). Among patients with inadequate response to prior anti-TNF agents, vedolizumab, or both at baseline, treatment effects favored ozanimod vs placebo on these endpoints in all three groups during both induction and maintenance.Ozanimod improved clinical, endoscopic, and histologic outcomes in both biologic-exposed and -naïve patients. Patients with prior biologic use may require additional time to respond to treatment. Outcomes were improved with ozanimod regardless of prior use of anti-TNF agents and vedolizumab.
To describe the demographic and clinical features and outcomes for children and adolescents with primary CNS lymphoma (PCNSL).A retrospective series of children and adolescents with PCNSL was assembled from 10 cancer centers in 3 countries.Twenty-nine patients with a median age of 14 years were identified. Sixteen (55%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or greater. Frontline therapy consisted of chemotherapy only in 20 patients (69%), while 9 (31%) had chemotherapy plus cranial radiotherapy. Most patients received methotrexate (MTX)-based regimens. Overall response rate was 86% (complete remission 69%, partial remission 17%). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 61% and 86%, respectively; the 3-year OS was 82%. Univariate analyses were conducted for age (≤ 14 vs. >14 years), PS (0 or 1 vs. >1), deep brain lesions, MTX dose, primary treatment with chemotherapy alone, intrathecal chemotherapy, and high-dose therapy. Primary treatment with chemotherapy alone was associated with better overall response rates with an odds ratio (OR) of 0.125 (P = 0.02). There was a marginally significant relationship between higher doses of MTX and response (OR = 1.5, P = 0.06). ECOG-PS of 0 to 1 was the only factor associated with better outcome with hazard ratios of 0.136 (P = 0.017) and 0.073 (P = 0.033) for PFS and OS, respectively.This is the largest series collected of pediatric PCNSL. The outcome of children and adolescents seems to be better than in adults. PS of 0 to 1 is associated with better survival.
We used a post-embedding immunoelectron microscopy method, using protein A-gold, to detect calcitonin and chromogranin A immunoreactivity in three cases of human medullary thyroid carcinoma. Because the epoxy-embedded tissue had been fixed (glutaraldehyde or formaldehyde) and osmicated before embedment, the proteins were identified in optimally preserved tissue. Uranyl and lead staining was used after immunolabeling, so that the tissue was also optimally contrasted. The morphological advantage provided by osmication was tested by labeling rat thyroid gland C-cells for calcitonin. The protein A-gold technique allowed localization of both antigens to the contents of membrane-bound secretory granules in the tumor cells. In one case, labeling density for each antigen was measured over several intercellular compartments and the interstitium. Calcitonin, but not chromogranin A, reactivity was also identified in intracellular amyloid fibrils in two cases, showing that the constant region of calcitonin is preserved in amyloid deposits related to the tumor cells.
Introduction: Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, demonstrated superior efficacy and safety vs placebo (PBO) for up to 52 weeks (wks) in adults with moderately to severely active ulcerative colitis (UC) in a phase 3 study (True North). In this post-hoc analysis, we evaluated the impact of prior biologic exposure on response to ozanimod. Methods: True North consisted of two cohorts. In cohort 1, patients (pts) with UC received double-blind treatment with once-daily ozanimod HCl 1 mg (equivalent to ozanimod 0.92 mg) or PBO. In cohort 2, pts received open-label once daily ozanimod HCl 1 mg. Ozanimod responders after a 10-wk induction were re-randomized to double-blind maintenance with ozanimod 1 mg or PBO through wk 52 (maintenance). Outcomes based on prior biologic exposure (biologic-naïve, 1 biologic, and 2+ biologics) were analyzed for clinical remission, clinical response, endoscopic improvement, and mucosal healing. Pts exposed to only a JAK inhibitor were excluded. Results: A total of 992 pts (n=213 PBO and n=426 ozanimod in cohort 1, n=353 ozanimod in cohort 2) were included in the analysis for induction; 616 were biologic-naïve, 162 had exposure to 1 biologic, and 214 were exposed to 2 or more biologics. At baseline, biologic-exposed pts had more prior corticosteroid use, longer disease duration, and more extensive disease than biologic-naïve pts. During induction, greater therapeutic effects of ozanimod were generally seen in biologic-naïve vs biologic-exposed pts; however, clinical remission and clinical response were similar for pts exposed to 1 biologic and biologic-naïve pts (Table 1). Compared with PBO, ozanimod-treated pts had greater responses on nearly all endpoints at wk 10 (cohort 1). Proportions were higher with ozanimod in cohort 2 than in cohort 1. During maintenance, ozanimod-treated pts had greater responses on all endpoints versus PBO, with similar proportions of pts achieving clinical response to ozanimod regardless of prior biologic exposure (Table 1). At wk 52, the proportion of pts on ozanimod with clinical remission was similar in the 1-biologic and 2+-biologic exposure groups, and proportions of pts on ozanimod with endoscopic improvement and mucosal healing were similar for the 1-biologic and biologic-naïve groups. Conclusion: Ozanimod improved clinical, endoscopic, and histologic outcomes in both biologic-exposed and -naïve pts. Pts with prior biologic use may require additional time to respond to treatment.Table 1.: Efficacy Outcomes in the Induction and Maintenance Trials.
Breast density is associated with reduced imaging resolution in the detection of breast cancer. A biochemical approach that is not affected by density would provide an important tool to healthcare professionals who are managing women with dense breasts and suspicious imaging findings. Videssa® Breast is a combinatorial proteomic biomarker assay (CPBA), comprised of Serum Protein Biomarkers (SPB) and Tumor Associated Autoantibodies (TAAb) integrated with patient-specific clinical data to produce a diagnostic score that reliably detects breast cancer (BC) as an adjunctive tool to imaging. The performance of Videssa® Breast was evaluated in the dense (a and b) and non-dense (c and d) groups in a population of n = 545 women under age 50. The sensitivity and specificity in the dense breast group were calculated to be 88.9% and 81.2%, respectively, and 92.3% and 86.6%, respectively, for the non-dense group. No significant differences were observed in the sensitivity (p = 1.0) or specificity (p = 0.18) between these groups. The NPV was 99.3% and 99.1% in non-dense and dense groups, respectively. Unlike imaging, Videssa® Breast does not appear to be impacted by breast density; it can effectively detect breast cancer in women with dense and non-dense breasts alike. Thus, Videssa® Breast provides a powerful tool for healthcare providers when women with dense breasts present with challenging imaging findings. In addition, Videssa® Breast provides assurance to women with dense breasts that they do not have breast cancer, reducing further anxiety in this higher risk patient population.
e22260 Background: Radiologists often experience difficulty in differentiating benign lesions from invasive breast cancers in patients assessed as BIRADS 3 or 4. Thus, a diagnostic test that would provide biochemical evidence to increase confidence in the patient’s clinical course is needed. Here, we present the a combinatorial biomarker panel for use in conjunction with imaging that increases the precise distinction between benign lesions and breast cancer. Methods: We have conducted two independent, multi-center, prospective clinical trials to establish the clinical validity of a breast cancer biomarker assay that uses a combination of Serum Protein Biomarkers (SPB), Tumor-Associated Autoantibodies (TAAb) with patient specific data to differentiate patients with benign breast disease from those with invasive breast cancer (IBC). Panels of biomarkers and associated algorithms were developed using prospectively collected samples from women under age 50 (n = 351) and from women ages 25-75 (n = 508). Results: The combination of the 001 and 002 trial data sets followed by multiple rounds of cross-validation resulted in a more sensitive and specific breast biomarker assay. Importantly, the ability to distinguish between benign and IBC/DCIS was not affected by breast density in either patient population. Conclusions: We note that breast biopsy decision making would benefit from the addition of blood-based biomarker testing. Given the high negative-predictive value of the biomarker test, a negative biomarker test can be interpreted as the patient being likely to have a benign condition. While the use of blood-based biomarker testing can never supersede breast imaging as a screening modality, it can provide additional biological information for patients with questionable lesions discovered on imaging. The combination of blood-based biomarker testing with traditional imaging can help improve diagnostic accuracy and patient follow-up, and likely reduce the number of biopsies performed. Clinical trial information: NCT02078570.
