Ibrutinib as first-line therapy for mantle cell lymphoma: a multicenter, real-world UK study.

ABSTRACT: During the COVID-19 pandemic, ibrutinib with or without rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. Because limited data are available in this setting, we conducted an observational cohort study evaluating safety and efficacy. Adults receiving ibrutinib with or without rituximab for untreated MCL were evaluated for treatment toxicity, response, and survival, including outcomes in high-risk MCL (TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 ≥ 30%). A total of 149 patients from 43 participating centers were enrolled: 74.1% male, median age 75 years, 75.2% Eastern Cooperative Oncology Group status of 0 to 1, 36.2% high-risk, and 8.9% autologous transplant candidates. All patients received ≥1 cycle ibrutinib (median, 8 cycles), 39.0% with rituximab. Grade ≥3 toxicity occurred in 20.3%, and 33.8% required dose reductions/delays. At 15.6-month median follow-up, 41.6% discontinued ibrutinib, 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2%, respectively. ORR was 77.3% (low risk) vs 59.0% (high risk) (P = .05) and 78.7% (ibrutinib-rituximab) vs 64.9% (ibrutinib; P = .13). Median progression-free survival (PFS) was 26.0 months (all patients); 13.7 months (high risk) vs not reached (NR) (low risk; hazard ratio [HR], 2.19; P = .004). Median overall survival was NR (all); 14.8 months (high risk) vs NR (low risk; HR, 2.36; P = .005). Median post-ibrutinib survival was 1.4 months, longer in 41.9% patients receiving subsequent treatment (median, 8.6 vs 0.6 months; HR, 0.36; P = .002). Ibrutinib with or without rituximab was effective and well tolerated as first-line treatment of MCL, including older and transplant-ineligible patients. PFS and OS were significantly inferior in one-third of patients with high-risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups.

A nationwide analysis of disparities in guideline-concordant care in American Indians and Alaska Natives with stage I non-small cell lung cancer.

Background: Several studies have shown racial disparities in lung cancer care in the United States in the Black and Hispanic populations but not many have included American Indian/Alaska Native (AI/AN) patients. We retrospectively evaluated the factors associated with receipt of guideline-concordant care in AI/AN and non-Hispanic White (NHW) patients with stage I non-small cell lung cancer (NSCLC) and describe the relationship between guideline-concordant care and survival outcomes in these populations. Methods: Using the National Cancer Database, we identified NHW and AI/AN patients diagnosed with stage I NSCLC between 2004 and 2017. We evaluated the utilization of anatomic resection among both NHW and AI/AN and described the variables associated with anatomic resection. We also evaluated 5-year overall survival (OS) by treatment and race. We used the chi-square test, multivariable analysis, and the Kaplan-Meier method for statistical analysis. Results: We identified 196,349 patients. Of these, 195,736 (99.69%) were NHW and 613 (0.31%) were AI/AN. Relative to NHW, AI/AN were more frequently diagnosed at a younger age (40% vs. 28% diagnosed at 18-64 years of age; P<0.001) and more commonly resided in rural areas (14% vs. 5%; P<0.001). In our multivariable analysis adjusting for all patient factors [age at diagnosis, sex, race, residence location, Charlson Comorbidity Index (CCI), tumor stage, lymph node status, and treatment facility], AI/AN patients were less likely to undergo anatomic resection than NHW patients [odds ratio (OR), 0.74; 95% confidence interval (CI): 0.62-0.89]. In our unadjusted survival analysis, AI/AN patients had lower 5-year OS than NHW (58% vs. 56%; P=0.04). When adjusted for surgery this difference was no longer significant. Conclusions: AI/AN patients with stage I NSCLC undergo anatomic resection less frequently than do NHW, with lower 5-year OS than NHW. However, this survival difference is mitigated when AI/AN undergo anatomic resection.

Disparities in post-mastectomy reconstruction use among American Indian and Alaska Native women.

BACKGROUND: American Indian/Alaska Native (AI/AN) breast cancer patients undergo post-mastectomy reconstruction (PMR) infrequently relative to Non-Hispanic White (NHW) patients. Factors associated with low PMR rates among AI/AN are poorly understood. We sought to describe factors associated with this disparity in surgical care. METHODS: A retrospective cohort study of the National Cancer Database (2004 - 2017) identified AI/AN and NHW women, ages 18 - 64, who underwent mastectomy for stage 0 - III breast cancer. Patient characteristics, annual PMR rates, and factors associated with PMR were described with univariable analysis, the Cochran-Armitage test, and multivariable logistical regression. RESULTS: 414,036 NHW and 1,980 AI/AN met inclusion criteria. Relative to NHW, AI/AN had more comorbidities (20% vs 12% Charlson Comorbidity Index ≥ 1, p < 0.001), had non-private insurance (49% vs 20%, p < 0.001), and underwent unilateral mastectomy more frequently (69% vs 61%, p < 0.001). PMR rates increased over the study period, from 13% to 47% for AI/AN and from 29% to 62% for NHW (p <0.001). AI/AN race was independently associated with decreased likelihood of PMR (OR 0.62, 95% CI 0.56-0.69). Among AI/AN, decreased likelihood of PMR was significantly associated with older age at diagnosis, more remote year of diagnosis, advanced disease (tumor size > 5 cm, positive lymph nodes), unilateral mastectomy, non-private insurance, and lower educational attainment in patient's area of residence. CONCLUSION: PMR rates among AI/AN with stage 0 - III breast cancer have increased, yet remain significantly lower than among NHW. Further research should elicit AI/AN perspectives on PMR, and guide early breast cancer detection and treatment.

Evaluating Disparities in Colon Cancer Survival in American Indian/Alaskan Native Patients Using the National Cancer Database.

BACKGROUND: Studies demonstrate higher mortality rates from colon cancer in American Indian/Alaskan Native (AI/AN) patients compared to non-Hispanic White (nHW). We aim to identify factors that contribute to survival disparities. METHODS: We used the National Cancer Database to identify AI/AN (n = 2127) and nHW (n = 527,045) patients with stage I-IV colon cancer from 2004 to 2016. Overall survival among stage I-IV colon cancer patients was estimated by Kaplan-Meier analysis; Cox proportional hazard ratios were used to identify independent predictors of survival. RESULTS: AI/AN patients with stage I-III disease had significantly shorter median survival than nHW (73 vs 77 months, respectively; p < 0.001); there were no differences in survival for stage IV. Adjusted analyses demonstrated that AI/AN race was an independent predictor of higher overall mortality compared to nHW (HR 1.19, 95% CI 1.01-1.33, p = 0.002). Importantly, compared to nHW, AI/AN were younger, had more comorbidities, had greater rurality, had more left-sided colon cancers, had higher stage but lower grade tumors, were less frequently treated at an academic facility, were more likely to experience a delay in initiation of chemotherapy, and were less likely to receive adjuvant chemotherapy for stage III disease. We found no differences in sex, receipt of surgery, or adequacy of lymph node dissection. CONCLUSION: We found patient, tumor, and treatment factors that potentially contribute to worse survival rates observed in AI/AN colon cancer patients. Limitations include the heterogeneity of AI/AN patients and the use of overall survival as an endpoint. Additional studies are needed to implement strategies to eliminate disparities.

Localization of the kinase Ataxia Telangiectasia Mutated to Adenovirus E4 mutant DNA replication centers is important for its inhibitory effect on viral DNA accumulation.

Adenovirus (Ad) type 5 (Ad5) E4 deletion mutants including H5dl1007 (E4-) induce a DNA damage response (DDR) that activates the kinase ataxia-telangiectasia mutated (ATM), which can interfere with efficient viral DNA replication. We find that localization of active phosphorylated ATM (pATM) to E4- viral replication centers (VRCs) is important for its inhibitory effect. ATM is necessary for localization of RNF8 and 53BP1 to E4 mutant VRCs, while recruitment of DDR factors Mre11, Mdc1 and γH2AX is ATM-independent, raising the possibility that ATM may affect viral chromatin at VRCs. We assessed E4- and Ad5 chromatin organization by micrococcal nuclease (MN) digestion. A significant fraction of Ad5 DNA is somewhat resistant to MN digestion, whereas E4- DNA is more susceptible. ATM inhibition increases the fraction of E4- DNA that is resistant to MN digestion. Our results address possible mechanisms through which ATM inhibits E4- DNA replication.

A critical role for donor-derived IL-22 in cutaneous chronic GVHD.

Graft-versus-host disease (GVHD) is the major cause of nonrelapse morbidity and mortality after allogeneic stem cell transplantation (allo-SCT). Prevention and treatment of GVHD remain inadequate and commonly lead to end-organ dysfunction and opportunistic infection. The role of interleukin (IL)-17 and IL-22 in GVHD remains uncertain, due to an apparent lack of lineage fidelity and variable and contextually determined protective and pathogenic effects. We demonstrate that donor T cell-derived IL-22 significantly exacerbates cutaneous chronic GVHD and that IL-22 is produced by highly inflammatory donor CD4+ T cells posttransplantation. IL-22 and IL-17A derive from both independent and overlapping lineages, defined as T helper (Th)22 and IL-22+ Th17 cells. Donor Th22 and IL-22+ Th17 cells share a similar IL-6-dependent developmental pathway, and while Th22 cells arise independently of the IL-22+ Th17 lineage, IL-17 signaling to donor Th22 directly promotes their development in allo-SCT. Importantly, while both IL-22 and IL-17 mediate skin GVHD, Th17-induced chronic GVHD can be attenuated by IL-22 inhibition in preclinical systems. In the clinic, high levels of both IL-17A and IL-22 expression are present in the skin of patients with GVHD after allo-SCT. Together, these data demonstrate a key role for donor-derived IL-22 in patients with chronic skin GVHD and confirm parallel but symbiotic developmental pathways of Th22 and Th17 differentiation.

Peroxynitrite mediates testosterone-induced vasodilation of microvascular resistance vessels.

Our knowledge of how androgens influence the cardiovascular system is far from complete, and this lack of understanding is especially true of how androgens affect resistance vessels. Our aim was to identify the signaling mechanisms stimulated by testosterone (TES) in microvascular arteries and to understand how these mechanisms mediate TES-induced vasodilation. Mesenteric microvessels were isolated from male Sprague-Dawley rats. Tension studies demonstrated a rapid, concentration-dependent, vasodilatory response to TES that did not involve protein synthesis or aromatization to 17ß-estradiol. Dichlorofluorescein fluorescence and nitrotyrosine immunoblot experiments indicated that TES stimulated peroxynitrite formation in microvessels, and functional studies demonstrated that TES-induced vasodilation was inhibited by scavenging peroxynitrite. As predicted, TES enhanced the production of both peroxynitrite precursors (i.e., superoxide and nitic oxide), and xanthine oxidase was identified as the likely source of TES-stimulated superoxide production. Functional and biochemical studies indicated that TES signaling involved activity of the phosphoinositide 3 (PI3) kinase-protein kinase B (Akt) cascade initiated by activation of the androgen receptor and culminated in enhanced production of cGMP and microvascular vasodilation. These findings, derived from a variety of analytical and functional approaches, provide evidence for a novel nongenomic signaling mechanism for androgen action in the microvasculature: TES-stimulated vasodilation mediated primarily by peroxynitrite formed from xanthine oxidase-generated superoxide and NO. This response was associated with activation of the PI3 kinase-Akt signaling cascade initiated by activation of the androgen receptor. We propose this mechanism could account for TES-stimulated cGMP production in microvessels and, ultimately, vasodilation.

Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis.

OBJECTIVE: We sought to determine whether vitamin D status is associated with developing new T2 lesions or contrast-enhancing lesions on brain magnetic resonance imaging (MRI) in relapsing multiple sclerosis (MS). METHODS: EPIC is a 5-year longitudinal MS cohort study at the University of California at San Francisco. Participants had clinical evaluations, brain MRI, and blood draws annually. From the overall cohort, we evaluated patients with clinically isolated syndrome or relapsing-remitting MS at baseline. In univariate and multivariate (adjusted for age, sex, ethnicity, smoking, and MS treatments) repeated measures analyses, annual 25-hydroxyvitamin D levels were evaluated for their association with subsequent new T2-weighted and gadolinium-enhancing T1-weighted lesions on brain MRI, clinical relapses, and disability (Expanded Disability Status Scale [EDSS]). RESULTS: A total of 2,362 3T brain MRI scans were acquired from 469 subjects. In multivariate analyses, each 10ng/ml higher 25-hydroxyvitamin D level was associated with a 15% lower risk of a new T2 lesion (incidence rate ratio [IRR], 0.85; 95% confidence interval [CI], 0.76-0.95; p = 0.004) and a 32% lower risk of a gadolinium-enhancing lesion (IRR, 0.68; 95% CI, 0.53-0.87; p = 0.002). Each 10ng/ml higher vitamin D level was associated with lower subsequent disability (-0.047; 95% CI, -0.091 to -0.003; p = 0.037). Higher vitamin D levels were associated with lower, but not statistically significant, relapse risk. Except for the EDSS model, all associations were stronger when the within-person change in vitamin D level was the predictor. INTERPRETATION: Vitamin D levels are inversely associated with MS activity on brain MRI. These results provide further support for a randomized trial of vitamin D supplementation.

Empirical evidence of the effectiveness of concept mapping as a learning intervention for nuclear medicine technology students in a distance learning radiation protection and biology course.

UNLABELLED: Metacognitive learning strategies are based on instructional learning theory, which promotes deep, meaningful learning. Educators in a baccalaureate-level nuclear medicine technology program demonstrated that students enrolled in an online, distance learning section of an introductory radiation protection and radiobiology course performed better when traditional instruction was supplemented with nontraditional metacognitive learning strategies. METHODS: The metacognitive learning strategy that was used is best known as concept mapping. The concept map, in addition to the standard homework problem assignment and opportunity for question-answer sessions, became the template for misconception identification and remediation interactions between the instructor and the student. The control group relied on traditional homework problems and question-answer sessions alone. Because students in both the "treatment" groups (i.e., students who used concept mapping) and the control group were distance learning students, all personal communications were conducted via e-mail or telephone. The final examination of the course was used to facilitate a quantitative comparison of the performance of students who used concept mapping and the performance of students who did not use concept mapping. RESULTS: The results demonstrated a significantly higher median final examination score for the concept mapping group than for the non-concept mapping group (z = -2.0381, P = 0.0415), with an appropriately large effect size (2.65). CONCLUSION: Concept mapping is a cognitive learning intervention that effectively enables meaningful learning and is suitable for use in the independent learner-oriented distance learning environments used by some nuclear medicine technology programs.

Dual-modality in vivo monitoring of subventricular zone stem cell migration and metabolism.

Rat subventricular zone (SVZ) stem cells were labeled with superparamagnetic iron oxide particles (SPIO) to follow their fate and migratory potential with magnetic resonance imaging (MRI) and positron emission tomography (PET). Labeled cells were transplanted into either the right rostral migratory stream (RMS) or striatum of normal adult Sprague-Dawley rats and serially followed for 3 months. Minimal migration of the cells implanted into the striatum was observed after 3 weeks whereas SVZ cells implanted into the RMS migrated toward the olfactory bulb at 1 week post-transplantation. PET studies of glucose metabolism using (18)F-FDG demonstrated enhanced glucose utilization in the striatum of transplanted animals. PET studies conducted 3 months after transplantation showed elevated accumulation of (11)C-raclopride (dopamine receptor type 2) and (11)C-CFT (dopamine transporter) binding in the striatal grafts. Implanted SVZ cells did not induce significant inflammation as identified by PET using (11)C-PK11195, a ligand detecting activated microglia. Histological analysis identified viable SPIO-labeled cells (some of which were nestin-positive) 7 weeks post-transplantation, suggesting a prolonged presence of undifferentiated neural stem cells within transplants. In addition, double immunostaining for neuronal and astrocytic markers (NeuN and GFAP) indicated that differentiation into neuronal and astrocytic phenotypes also occurred. Thus, combining MRI and PET enables monitoring of cell migration and metabolism non-invasively in vivo for extended periods of time.