Citations

Introduction: Bortezomib has been reported to favourably impact the outcomes of t(4;14) and del(17p) in multiple myeloma (MM), but its impact on gain 1q (+1q) is unknown. Methods: To address this, 250 patients treated with bortezomib-based induction were analysed. All myeloma samples had fluorescence in situ hybridization (FISH) performed on CD138-sorted bone marrow aspirate, and plasma cells were analysed using DNA probes specific for the following chromosomal aberrations: del(13q14), del(17p), t(14;16), t(4;14), and +1q. Presence of +1q was defined as the presence of at least three copies of 1q21 at the cut off level of 20% of bone marrow plasma cells. Results: +1q identified in 167 (66.8%) and associated with t(4;14) and high lactate dehydrogenase (LDH). +1q was not associated with response rate but shorter event-free survival (EFS) (median EFS 35 vs 55 months, p = 0.05) and overall survival (OS) (median OS 74 vs 168 months, p = 0.00025). Copy number and clone size did not impact survival. Multivariate analysis showed +1q was an independent adverse factor for OS together with International Staging System (ISS)3, high LDH, del(17p) and t(4;14). When a risk score of 1 was assigned to each independent adverse factor, OS was shortened incrementally by a risk score from 0 to 4. Post-relapse/progression survival was inferior in those with +1q (median 60 vs 118 months, p = 0.000316). Autologous stem cell transplantation (ASCT) improved OS for those with +1q (median OS 96 vs 49 months, p = 0.000069). Conclusion: +1q is an adverse factor for OS in MM uniformly treated with bortezomib-based induction but was partially mitigated by ASCT. A risk scoring system comprising +1q, LDH, high-risk FISH, and ISS is a potential tool for risk stratification in MM.

Abstract Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib–rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.

Background: Cranial dural arteriovenous fistulas with cortical venous drainage are rare lesions that can present with hemorrhage. A high rate of rebleeding in the early period following hemorrhage has been reported, but published long-term rates are much lower. No study has examined how risk of rebleeding changes over time. Our objective was to quantify the relative incidence of rebleeding in the early and later periods following hemorrhage. Methods: Patients with dural arteriovenous fistula and cortical venous drainage presenting with hemorrhage were identified from the multinational CONDOR (Consortium for Dural Fistula Outcomes Research) database. Natural history follow-up was defined as time from hemorrhage to first treatment, rebleed, or last follow-up. Rebleeding in the first 2 weeks and first year were compared using incidence rate ratio and difference. Results: Of 1077 patients, 250 met the inclusion criteria and had 95 cumulative person-years natural history follow-up. The overall annualized rebleed rate was 7.3% (95% CI, 3.2–14.5). The incidence rate of rebleeding in the first 2 weeks was 0.0011 per person-day; an early rebleed risk of 1.6% in the first 14 days (95% CI, 0.3–5.1). For the remainder of the first year, the incidence rate was 0.00015 per person-day; a rebleed rate of 5.3% (CI, 1.7–12.4) over 1 year. The incidence rate ratio was 7.3 (95% CI, 1.4–37.7; P , 0.026). Conclusions: The risk of rebleeding of a dural arteriovenous fistula with cortical venous drainage presenting with hemorrhage is increased in the first 2 weeks justifying early treatment. However, the magnitude of this increase may be considerably lower than previously thought. Treatment within 5 days was associated with a low rate of rebleeding and appears an appropriate timeframe.

AbstractFrontline arsenic trioxide (ATO)–based treatment regimens achieve high rates of long-term relapse-free survival in treating acute promyelocytic leukemia (APL) and form the current standard of care. Refining prognostic estimates for newly diagnosed patients treated with ATO-containing regimens remains important in continuing to improve outcomes and identify patients who achieve suboptimal outcomes. We performed a pooled analysis of exclusively ATO-treated patients at a single academic institution and from the ALLG APML4 and Alliance C9710 studies to determine the prognostic importance of additional cytogenetic abnormalities and/or complex karyotype. We demonstrated inferior event-free survival for patients harboring complex karyotype (hazard ratio [HR], 3.74; 95% confidence interval [CI], 1.63-8.56; P = .002), but not for patients harboring additional cytogenetic abnormalities (HR, 2.13; 95% CI, 0.78-5.82; P = .142). These data support a role for full karyotypic analysis of all patients with APL and indicate a need for novel treatment strategies to overcome the adverse effect of APL harboring complex karyotype.

AbstractImmune checkpoint inhibitors (ICIs), as a novel class of anticancer therapy, can be more efficacious and less toxic than chemotherapy, but their clinical success is confined to certain tumor types. Elucidating their targets, mechanisms and scope of action, and potential synergism with chemotherapy and/or targeted therapies are critical to widen their clinical indications. Treatment response to an ICI targeting programmed death‐1 (anti‐PD‐1) is sought to be understood here by conducting a preplanned correlative analysis of a phase II clinical trial in patients with small bowel adenocarcinoma (SBA). The cytolytic capacity of circulating immune cells in cancer patients using a novel ex vivo cytotoxicity assay is evaluated, and the utility of circulating biomarkers is investigated to predict and monitor the treatment effect of anti‐PD‐1. Baseline expression of Bim and NKG7 and upregulation of CX3CR1 in circulating T cells are associated with the clinical benefit of anti‐PD‐1 in patients with SBA. Overall, these findings suggest that the frequency and cytolytic capacity of circulating, effector immune cells may differentiate clinical response to ICIs, providing a strong rationale to support immune monitoring using patient peripheral blood.

Abstract Context Metastatic pheochromocytomas and paragangliomas (mPPGL) are rare vascular neuroendocrine tumors that highly express vascular growth factors. Systemic treatment options in cases of unresectable multisite disease are limited. Multikinase inhibitors that inhibit angiogenesis, such as lenvatinib, have proven effective in several other malignancies, and may be a viable option for mPPGL. Objective We aimed to evaluate the efficacy of lenvatinib as salvage therapy in mPPGLs. Methods This was a retrospective analysis of mPPGL patients ≥ 18 years of age who received lenvatinib from 2015 to 2020 at a tertiary referral center. Patients were started on lenvatinib 20 mg daily and dose was adjusted according to tolerance or disease progression. Results Eleven patients were included. Median treatment duration was 14.7 months (95% CI, 2.3-NE). Treatment was discontinued due to disease progression, adverse events, or death. Overall survival at 12 months was 80.8% (95% CI, 42.3-94.9%) but its median was not reached. Median progression-free survival was 14.7 months (95% CI, 1.7-NE). Among the 8 patients with measurable disease, overall response rate was 63%, as 5/8 experienced a partial response and 3/8 had stable disease. Worsening hypertension and anemia were the most common adverse events. Conclusion Lenvatinib may be a viable treatment option for mPPGL, although at the potential risk of worsening hypertension. Larger, multicenter studies are needed to better characterize treatment efficacy.

Introduction: The selection of acute ischemic stroke patients relies on the interpretation of radiological studies, commonly including noncontrast CT (ASPECTS score), CTA, and in some circumstances, CT perfusion (CTP) scans. Hypothesis: The interrater reliability between readers of noncontrast head CT will be moderate and not as good as that between readers of CT perfusion scans. Methods: Retrospective study of consecutive ischemic stroke patients who were considered for endovascular stroke therapy at an academic medical center from April 2010 - November 2014. All patients underwent CT, CTA, and CTP. Images were independently reviewed by four readers (A, B, C, D) in total (2 experienced neuroradiologists, one experienced neurointensivist, and one neuroradiology fellow). Each rated half of the cohort. All readers performed online training in ASPECTS. Moderate-to-good collateral circulation was defined as filling of 50% or more of the middle cerebral artery pial arterial territory on CTA, as in ESCAPE trial. An “acceptable core” on CTP was defined as in EXTEND-IA trial with core volume < 70 mL, mismatch ratio >1.2, and absolute mismatch volume >10 mL but was qualitatively estimated. Interrater agreement was assessed for total ASPECTS, dichotomized ASPECTS (≥6 vs <6), evaluation of collaterals, and evaluation of core. Agreement was assessed using kappa statistic, which was weighted for the total ASPECTS analysis. Results: Our cohort included 119 patients with acute stroke and large vessel occlusion. Interrater agreement for total ASPECTS was very good between readers C and D (' 0.70) and good between A and B (' 0.55). For dichotomized ASPECTS, agreement was fair-to-good (' 0.30 for C/D; ' 0.41 for A/B). Agreement for grading collaterals on CTA was good to very good (' 0.64 for C /D; ' 0.54 for A/B). Agreement for rating core on CTP was very good (' 0.78 for C/D; ' 0.62 for A/D). Conclusions: Interrater reliability is good to very good for total ASPECTS score, dichotomous grading of collaterals on CTA, and subjective estimation of core size on CTP. Agreement is only fair to good for dichotomized ASPECTS.

Objective: Controversy exists as to whether platelet inhibition testing is necessary prior to aneurysm treatment in patients premedicated with antiplatelet agents. Using the IntrePED ( Int ernational Re trospective Study of P ipeline E mbolization D evice) registry, we studied complication rates in platelet-testing and non-platelet testing groups to determine if platelet testing is associated with improved outcomes. Materials and Methods: Patients with unruptured intracranial aneurysms from the INTREPED registry were divided into those who received platelet testing (testing group) and those who did not (nontesting group). Morbidity, mortality and thrombotic and hemorrhagic complication rates were studied. Comparisons between groups for continuous variables were evaluated using t -tests and Fisher’s exact test or Pearson’s chi-square for binary categorical variables. Multivariate logistic regression analysis was performed to determine if platelet function testing was independently associated with poor outcomes adjusting for age, number of devices, aneurysm location, size, and use of multiple exchange wires. Results: When compared to the non-testing group, the platelet testing group suffered higher rates of ipsilateral intracranial hemorrhage (12/511, 2.3% versus 0/187, 0.0%, P=0.04), neurological morbidity (42/511, 8.2% versus 4/187, 2.1%, P=0.01), and combined neurological morbidity and mortality (45/511, 8.8% versus 6/187, 3.2%, P=0.01). More patients in the testing group were treated with multiple PEDs (228 patients, 38.1% versus 57 patients, 28.4%, P=0.01). On multivariate analysis, the platelet testing group had a higher odds of total major morbidity (OR=3.80, 95%CI=1.30=11.08, P=0.01) and total major morbidity and neurological mortality (OR=2.74, 95%CI=1.11-6.79). Conclusion: Our findings caution against blind acceptance of platelet testing in Pipeline patients. Further prospective studies are needed to determine if and when platelet testing in Pipeline patients is appropriate.

Background: Pressure gradients across an intracranial stenosis, or fractional flow (FF), may identify the hemodynamic significance of symptomatic lesions. Computational fluid dynamic (CFD) simulations on 3D morphology of such lesions can calculate these pressure gradients and model effects of systemic physiology interacting with these lesions, such as hypotension and induced hypertension. We studied SAMMPRIS angiography to calculate FF across symptomatic intracranial stenoses and modeled the downstream effect of systemic blood pressure (BP) fluctuations. Methods: Conventional angiography of symptomatic intracranial stenoses in the SAMMPRIS trial was converted from biplanar images to a 3D geometric mesh. CFD simulations were conducted with Ansys CFX on a Cray supercomputer to calculate FF derived from distal/proximal pressure gradients for each of 3 inflow conditions: normal BP (120/80 mm Hg), hypotension (90/60 mm Hg) and hypertension (180/120 mm Hg). Abnormal FF was defined as ≤ 0.8 during diastole to define hemodynamic significance of a stenosis. Results: 407 patients with 70-99% symptomatic stenosis had conventional angiography with biplanar views available for 3D reconstruction in 249, and CFD simulations in 188 (25 VA, 45 BA, 32 ICA, 86 MCA). Under simulated normal inflow conditions (120/80 mm Hg), only 76/188 (40%) cases had low FF. During simulated hypertension, FF improved to normal in 10/188 (5%) cases. Simulated hypotension caused FF to worsen from normal in 12/188 (6%) cases. Other hemodynamic parameters including shear stress could also be calculated and visually depicted in all cases. Conclusions: CFD and hemodynamic modeling of FF can be retrospectively performed after 3D conversion of biplanar angiogram views. FF estimates predict that only 40% of severe (70-99%) symptomatic intracranial stenoses are hemodynamically significant. Systemic BP fluctuations can be modeled during phases of the cardiac cycle to show downstream flow changes.

Background and Purpose- IV rt-PA has become a widely accepted treatment for a select group of patients with acute ischemic stroke. Quantifying the costs of hospitalization is important for understanding the economic impact of these patients on the hospitals that care for them. We evaluated recent data to determine costs associated with hospitalization for acute ischemic stroke patients treated with intravenous thrombolysis, including subgroup analysis to determine the effects of age and discharge status on hospital costs. Methods- Using the National Inpatient Sample, we evaluated the costs for hospitalization for patients treated with intravenous thrombolysis for acute ischemic stroke in the United States from 2001-2008. The primary endpoint examined in this study was total hospital costs, and these were correlated with clinical outcome. Costs were compared with 2008 Medicare reimbursement for intravenous thrombolysis without complication, and intravenous thrombolysis with major complication. Results- A total of 63472 patients received intravenous thrombolysis for acute ischemic stroke. 24094 patients were <65 years old and 40780 patients were ≥65 years old. Median hospital costs in 2008 dollars were $14102 (IQR $9987-$20819) for patients with good outcome, $18856 (IQR $13145-$30423) for patients with severe disability, and $19129 (IQR $11966-$30781) for patients with mortality. Average 2008 Medicare payments were $10,098 for intravenous thrombolysis without complication and $13,835 for intravenous thrombolysis with major complication. Conclusions- Our study of the NIS shows that hospitalization costs in the United States for ischemic stroke patients treated with intravenous thrombolysis are rather high. Medicare payments have not been adequate reimbursement for these hospitalizations. Hopefully, future reconciliation of costs with payments will be feasible, so that hospitals can afford to provide proper care for ischemic stroke patients treated with intravenous thrombolysis.