Citations

HIV is an independent risk factor for lung disease, including chronic obstructive pulmonary disease (COPD) and emphysema. Angiotensin receptor blockers may be beneficial in COPD and emphysema through pathways that have been implicated in HIV-related lung disease. We performed a randomized comparison of the effects of losartan versus placebo on the plasma concentrations of the pneumoproteins, surfactant protein D (SPD) and club cell secretory protein (CCSP), in people living with HIV (PLWH). A total of 108 PLWH were included (52 assigned to losartan and 56 assigned to placebo). We found no difference in the change from baseline in log 2 concentrations of CCSP or SPD over 1 year of follow-up. For SPD, we found a strong interaction by CD4+ counts, where those with CD4+ counts >350 cells/mm 3 treated with losartan had more reduction (improvement) in SPD concentration than those treated with placebo ( p value for interaction <.001). In conclusion, we did not find a beneficial effect of losartan on pneumoprotein concentrations in PLWH, but PLWH with higher CD4+ counts may have improvement in SPD when treated with losartan.

Abstract Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q &lt; 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

2518 Background: This study sought to evaluate the prognostic significance of the three WHO-defined molecular glioma subgroups ( IDHwt, IDHmt/non-codel, and IDHmt/codel) in NRG Oncology/RTOG 0424, a phase II trial of high-risk low-grade gliomas treated with radiation (RT) and concurrent and adjuvant temozolomide (TMZ) after biopsy/surgical resection. Notably, this is the first clinical study to evaluate the prognostic value of the WHO subgroups in RT + TMZ-treated high-risk grade II (G2) gliomas using prospectively-collected long-term survival data. Methods: IDH1/2 mutation status was determined by next-generation sequencing. 1p/19q co-deletion status was determined by Oncoscan and/or 450K methylation data. Overall survival (OS) and progression-free survival (PFS) by marker status were determined by the Cox proportional hazard model and tested using the log-rank test in a post-hoc analysis. Patient pre-treatment characteristics were included as covariates in multivariate analyses. Results: Of all the eligible patients (N=129), 80 (62%) had sufficient quality DNA for both IDH and 1p/19q analyses. Of these 80, 54 (67.5%) were IDHmt, and 26 (32.5%) were IDHwt. Of the 54 IDHmt patients, 26 (32.5% of total, 48% of IDHmt) were IDHmt/codel, and 28 (35% of total, 52% of IDHmt) were IDHmt/non-codel. Both IDHmt subgroups were significantly correlated with longer PFS ( IDHmt/co-del = 8.1yrs (5.2-not reached (NR)); IDHmt/non-codel = 7.5yrs (3.9-11.8); IDHwt = 1.0yr (0.6-1.7), p<0.001) and OS ( IDHmt/co-del = 9.4yrs (8.2-NR); IDHmt/non-codel = 8.8yrs (5.9-NR); IDHwt = 2.3yrs (1.4-3.4), p<0.001) relative to the IDHwt subgroup. Upon univariate and multivariate analyses, both molecular IDHmt subgroup comparisons relative to IDHwt remained significant (p<0.001) even after incorporation of known clinical variables. Conclusions: These analyses suggest that G2 glioma patients harboring IDH1/2 mutations, regardless of co-deletion status, demonstrated longer survival with RT + TMZ relative to IDHwt tumors, although sample size is limited and analyses were post-hoc. These results also support the notion that outcomes for IDHwt high-risk G2 gliomas remain dismal (median = 2.3yrs, similar to G3 anaplastic astrocytoma); these patients should be separated from IDHmt patients in future G2 glioma trials, and warrant novel treatment strategies. Funding: U10CA180868, U10CA180822, U24CA196067, CURE, PA Dept. of Health, and Merck. Also, R01CA108633, R01CA169368, RC2CA148190, U10CA180850, BTFC, OSUCCC (all to AC). Clinical trial information: NCT00114140 .

Abstract Introduction: The NCIC CTG previously reported the results of a dose-finding trial testing the combination of Melphalan (M) and Lenalidomide (L) in previously untreated patients with multiple myeloma who were ineligible for stem cell transplantation because of older age and/or comorbidity (White, Blood2007; 110: 63a). Using a 28-day schedule, M (dose indicated as mg/m2/day given on days 1–4) and L (dose indicated in mg/day given on days 1–21) was associated with excess toxicity with the regimens M9L10, M4L15 and M6L10. We concluded that phase II testing of M5L10 was warranted and now report the results of this testing. Methods: Previously untreated symptomatic and consenting patients with tissue-confirmed plasmacytosis and a measurable M-protein were eligible provided that they had acceptable hematologic and biochemical laboratory parameters and no precluding comorbidities. Planned treatment consisted of M 5 mg/m2 days 1–4 and L 10 mg days 1–21, given every 28 days for 12 cycles. As our intent was to determine dose levels that could be given independently of G-CSF, primary prophylaxis with G-CSF was not included but use of G-CSF for established neutropenia was permitted. A hematologic dose limiting toxicity (H-DLT) was defined as the need for 2 dose attenuations of L or 1 dose attenuation of M occurring within the first 3 treatment cycles. Responses to treatment were classified using 1998 EBMT criteria and assessed after 2 and 6 cycles of therapy. Results: The intended sample size was 41 patients; 35 patients (1 ineligible) were enrolled before the study was closed due to observing a frequency of DLTs that surpassed predefined boundaries. Of the 34 eligible patients, median age was 73.4 yrs and ISS was stage I = 13, stage II = 11 and stage III = 10. Prior to study closure, 27 patients were evaluable for DLT; 7 (26%) did not experience a DLT. Among the remaining 20 (74%) patients, non-hematologic (N=2) and hematologic (N=18) DLTs requiring dose attenuations were seen within the first 3 treatment cycles; the H-DLTs included severe or prolonged neutropenia (N=11), thrombocytopenia (N=2) or both (N=5). One fatal serious adverse event was observed, this was due to a stroke. The other non-hematologic DLT was a cranial nerve III palsy which subsequently resolved. Responses after 2 cycles were evaluable in 21 patients and included partial response (PR) = 11, minimal response = 6, no change = 2 and progressive disease (PD) = 2. For those patients without PD after 2 cycles, responses after 6 cycles were evaluable in 8 and included PR = 6, stable response = 1 and PD = 1. Conclusion: Although M + L is an active combination for previously untreated myeloma patients, the regimen is associated with considerable myelosuppression. Without the routine use of GCSF, the doses used in the MY.11 study were not tolerable. Inability to use planned doses may have compromised the efficacy of the combination.

Abstract Introduction. The NCIC CTG is conducting phase II testing to establish the tolerability and estimate the efficacy of combining lenalidomide (L) + melphalan (M) over multiple cycles for previously untreated patients with multiple myeloma who are ineligible for stem cell transplantation. We report the data from the preliminary safety phase of this trial. Methods. The MY.11 trial was initially designed as a randomized phase II test of M 9 mg/m2 given on days 1–4 (M9) plus either L 10 mg (L10) or 20 mg given on days 1–21 of a 28 day cycle. Primary prophylaxis with G-CSF was not included, but use of G-CSF for established neutropenia was permitted; our intent was to determine dose levels that could be given independently of G-CSF. A dose attenuation schedule was developed for neutropenia and/or thrombocytopenia that was severe and occurred during the administration of L or was persistent and caused a delay in the next treatment cycle. A hematologic dose limiting toxicity (H-DLT) was defined as the need for 2 dose attenuations of L or 1 dose attenuation of M. Prior to the randomized phase of the trial, a safety run-in phase testing M9+L10 in 6 patients was planned; closure of this arm was to occur if, during the first 3 treatment cycles, there were ≥ 3 H-DLTs or any non-hematologic serious adverse event (SAE) judged to be treatment related. Four of the planned 6 patients were entered; during their first 3 treatment cycles, each experienced a H-DLT and one died from sepsis. The study was therefore amended with the intent to conduct a randomized phase II test of M 4 mg/m2 days 1–4 plus L 15 mg days 1–21 (M4L15) and M 6 mg/m2 days 1–4 plus L 10 mg days 1–21 (M6L10). Prior to the randomized phase of testing, each regimen was tested in non-randomized safety run-ins that included 6 patients per arm. The same parameters as above for study arm closure were applied. If the M6L10 arm was closed, the trial would proceed to test M 5 mg/m2 days 1–4 and L 10 mg days 1–21 (M5L10). Results. Six patients were enrolled to M4L15: during their first 3 treatment cycles, 4 patients experienced H-DLTs related to severe or persistent grade 3–4 neutropenia and one other patient experienced an SAE related to hallucinations and multiple constitutional complaints. This arm was therefore closed to accrual. Six patients were enrolled to M6L10: during their first 3 treatment cycles, 3 patients experienced H-DLTs related to severe or persistent grade 3–4 neutropenia. One of these patients was hospitalized with pulmonary edema and another with febrile neutropenia. This arm was therefore closed and the MY.11 trial amended to proceed as a single-arm phase II testing M5L10. Conclusion. Although M + L holds promise as an effective combination for previously untreated myeloma patients, the regimen is associated with considerable myelosuppression. The efficacy of the combination when given at tolerable doses remains to be established.

Abstract BACKGROUND Adding intensive-procarbazine, lomustine, and vincristine (iPCV) to radiotherapy (RT) prolonged progression-free (PFS) and overall survival (OS) for patients with 1p19q codeleted anaplastic oligodendroglial tumors (AOTs); some benefit was also observed for IDH-mutant non-codeleted cases (Cairncross et al 2013, 2014, 2016). Now, 25 years after study activation, we updated survival, further assessed IDH as a predictive biomarker, and are exploring the benefit from vincristine. METHODS Eligible adults (KPS ≥ 60, adequate end-organ function) were randomized to pre-RT iPCV (4 cycles x 6 weeks each) vs. RT alone, stratified by age (< or ≥ 50), KPS (60–70 or ≥ 80), and level of anaplasia. Histology (anaplastic oligodendroglioma/oligo-astrocytoma required) and biomarkers (IDH and 1p19q, post-hoc) were determined centrally. Survival was estimated by Kaplan-Meier and Hazard Ratios (HRs) by Cox-regression. RESULTS Overall (n=289), median follow-up was 16.4 years vs. 11.3 years at last report. In codeleted cases, 40% randomized to iPCV remained alive vs. 53% at last report; 5, 10, and 14 year-PFS and -OS rates were 62%, 50%, 41% and 70%, 57%, 46%, respectively; and iPCV unequivocally prolonged PFS (median 9.8 vs. 2.9 years, HR 0.46, 95% CI 0.3–0.7, p< 0.001) and OS (median 13.2 vs. 7.3 years, HR 0.61, 95% CI 0.40–0.94; p=0.02). With IDH mutation but without codeletion (n=66), iPCV prolonged PFS (median 2.8 vs. 1.9 years, HR 0.58, 95% CI 0.34–0.99, p=0.046); OS was longer with a trend for significance (median 5.5 vs. 3.3 years, HR 0.6, 95% CI 0.34–1.03, p=0.06) on this underpowered exploratory post-hoc analysis. CONCLUSION For codeleted AOTs, long-term analyses confirmed that pre-RT iPCV produced meaningful and significant prolongations of PFS and OS. With IDH mutation but without codeletion, iPCV significantly prolonged PFS and showed a trend for prolonged OS. The value of vincristine is being assessed. Supported by NCI grants U10CA180868, U10CA180822, U24CA196067, and UG1CA189867.

Abstract BACKGROUND A major impediment to improving neuro-oncology outcomes is poor clinical trial accrual. METHODS We convened a multi-stakeholder group including Society for Neuro-Oncology, Response Assessment in Neuro-Oncology, patient advocacy groups, clinical trial cooperative groups, and other partners to determine how we can improve trial accrual. RESULTS We described selected factors contributing to poor trial accrual and possible solutions. We focused on patient and community factors, disparities, physician and provider factors, clinical trial factors, and site and organizational factors CONCLUSIONS We will implement strategies with the intent to double accrual to neuro-oncology trials over the next 5 years.

Abstract Many factors contribute to the poor survival of malignant brain tumor patients, some of which are not easily remedied. However, one contributor to the lack of progress that may be modifiable is poor clinical trial accrual. Surveys of brain tumor patients and neuro-oncology providers suggest that clinicians do a poor job of discussing clinical trials with patients and referring patients for clinical trials. Yet, data from the Cancer Action Network of the American Cancer Society suggest that most eligible oncology patients asked to enroll on a clinical trial will agree to do so. To this end, the Society for Neuro-Oncology (SNO) in collaboration with the Response Assessment in Neuro-Oncology (RANO) Working Group, patient advocacy groups, clinical trial cooperative groups, including the Adult Brain Tumor Consortium (ABTC), and other partners are working together with the intent to double clinical trial accrual over the next 5 years. Here we describe the factors contributing to poor clinical trial accrual in neuro-oncology and offer possible solutions.