Outcomes with low dose anti-thymocyte globulin based graft versus host disease prophylaxis after mismatched unrelated donor allogeneic hematopoietic cell transplantation.

BACKGROUND: Anti-thymocyte globulin (ATG) based graft versus host disease (GVHD) prophylaxis is widely used for mismatched unrelated donor allogeneic hematopoietic cell transplantation (HCT) although optimal dose remains unclear. Although recent literature suggested improved outcomes with PTCy-based regimens when compared to ATG-based regimens these studies used doses of ATG ≥5 mg/kg. Thus, we analyzed outcomes of HLA 9/10 MMUD allogeneic HCTs using lower-dose ATG-based regimens at our center. METHODS: We retrospectively analyzed outcomes of HLA 9/10 MMUD allogeneic HCTs using lower dose ATG-based regimens for all adults undergoing allogeneic HCT at The Ottawa Hospital from 2015 to 2022. Data regarding demographics, conditioning regimen, dose of ATG, rates of GVHD, duration of remission, and survival, were collected and analyzed. RESULTS: Seventy-seven (n = 77) patients (males 62.3%; median age 50 years) underwent allogeneic HCT from MMUD. Majority(81%; n = 63) received 2.5 mg/kg of rabbit ATG and remaining 18.2% (n = 14) received 4.5 mg/kg. Grade II-IV acute GVHD occurred in 24.7% (n = 19) while any chronic GVHD occurred in 32.5% (n = 25) patients. After a median follow-up of 21 months, relapse occurred in 28.6% of patients. Two-year OS, GRFS, CIR, and NRM were 60.6%, 45.3%, 16.9%, and 18.2% respectively. Dose of ATG (2.5 mg/kg vs. 4.5 mg/kg) was not associated with outcomes in either univariate or multivariate analyses. CONCLUSIONS: When compared to published studies using ATG doses ≥5 mg/kg, GVHD prophylaxis using lower dose ATG may potentially lead to improved outcomes in patients undergoing MMUD allogeneic HCT. Further studies are needed to directly compare lower dose ATG to PTCy-based regimens to determine ideal GVHD prophylaxis for these patients.

Face validity of the Kids' ITP Tools (KIT) in the era of thrombopoietin receptor agonists.

The Kids' ITP Tools (KIT) is a questionnaire to assess quality of life of children with immune thrombocytopenia (ITP). The aim of this study was to update this previously validated tool to align with changes in clinical practice, specifically, treatment with thrombopoietin receptor agonists (TPO-RAs). Children aged 1-18 with ITP and/or their families were recruited to participate in interviews to review the KIT. Twenty-six interviews were conducted. Based on interview data from children and families, current guidelines, and expert opinion, five changes were made to the KIT in order to improve its face validity.

Predicting the Risks of Aggressive-Intent Chemotherapy Toxicity in Older Patients With Lymphoma: A Prospective Observational Pilot Study.

INTRODUCTION: Lymphoma is a disease of older patients and while treatment is subtype specific, curative or aggressive intent combination chemotherapy is often recommended. However, there has been limited evidence on which to base treatment decisions for older adults. Our objectives were to assess the utility of risk stratification measures and serial functional tests in predicting chemotherapy toxicity and as well the feasibility of conducting these in older adults undergoing chemotherapy for lymphoproliferative disorders. MATERIALS AND METHODS: This prospective cohort study recruited lymphoma patients 70 years or older planned for systemic chemotherapy. The Cancer and Aging Research Group (CARG) risk stratification tool and Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) were calculated at baseline. The Clinical Frailty Scale (CFS), Charlson Comorbidity Index score, grip strength and gait speed test, and toxicity events, were assessed at baseline and serially throughout treatment. Sarcopenia was calculated on CT scans at baseline, midway through treatment, and 1-month after completion of therapy. The primary endpoint was to assess the feasibility of applying these measures in busy ambulatory clinics. These measures were also correlated with clinical outcomes including ≥grade 3 adverse events (AEs), hospitalizations and emergency department visits, dose changes or delays, and overall survival. RESULTS: In total, 30 patients were enrolled (mean age 78.1 ± 6.4 years), of whom 20 were treated with curative intent. A total of 16 patients (53%) experienced grade ≥3 AEs, 9 (56%) of which led to a chemotherapy delay. On univariable analyses, CFS score, a high CARG score, medium to high CRASH score, and the gait speed were associated with grade ≥3 AEs, while only CFS remained significant on multivariable analysis. On univariable analysis, patients with a medium to high risk CRASH score were more likely than low risk patients to have an unplanned emergency department visit or hospitalization. CONCLUSIONS: The CFS seems to predict toxicity in this cohort study, with gait speed, CARG and CRASH scores being potentially additional predictive methods of evaluation.

Assessment of left ventricular function by CMR versus MUGA scans in breast cancer patients receiving trastuzumab: a prospective observational study.

Little is known about the comparison of multiple-gated acquisition (MUGA) scanning with cardiovascular magnetic resonance (CMR) for serial monitoring of HER2+ breast cancer patients receiving trastuzumab. The association of cardiac biomarkers with CMR left ventricular (LV) function and volume is also not well studied. Our objectives were to compare CMR and MUGA for left ventricular ejection fraction (LVEF) assessment, and to examine the association between changes in brain natriuretic peptide (NT-BNP) and troponin-I and changes in CMR LV function and volume. This prospective longitudinal two-centre cohort study recruited HER2+ breast cancer patients between January 2010 and December 2013. MUGA, CMR, NT-BNP and troponin-I were performed at baseline, 6, 12, and 18 months after trastuzumab initiation. In total, 41 patients (age 51.7 ± 10.8 years) were enrolled. LVEF comparison between MUGA and CMR demonstrated weak agreement (Lin's correlation coefficient r = 0.46, baseline; r = 0.29, 6 months; r = 0.42, 12 months; r = 0.39, 18 months; all p < 0.05). Bland-Altman plots demonstrated wide LVEF agreement limits (pooled agreement limits 3.0 ± 6.2). Both modalities demonstrated significant LVEF decline at 6 and 12 months from baseline, concomitant with increased LV volumes on CMR. Changes in NT-BNP correlated with changes in LV diastolic volume at 12 and 18 months (p < 0.05), and LV systolic volume at 18 months (p < 0.05). Changes in troponin-I did not correlate with changes in LV function or volume at any timepoint. In conclusion, CMR and MUGA LVEF are not interchangeable, warranting selection and utility of one modality for serial monitoring. CMR is useful due to less radiation exposure and accuracy of LV volume measurements. Changes in NT-BNP correlated with changes in LV volumes.

Intravenous iron versus oral iron or observation for gastrointestinal malignancies: a systematic review.

BACKGROUND: Anemia is a common condition in patients with gastrointestinal cancer. Current evidence for the use of intravenous compared with oral iron in this clinical setting is inconclusive. A systematic review was performed to assess evidence on the efficacy of intravenous iron versus oral/observation in gastrointestinal cancer patients in the preoperative and postoperative setting. MATERIALS AND METHODS: We searched Medline and Embase from inception until December 2017 with no language restrictions. Outcomes included hemoglobin response, red blood cell transfusion, and adverse events. Screening, data abstraction, and risk of bias appraisal were performed by two independent reviewers. The risk of bias was assessed using the Cochrane tools for randomized and nonrandomized studies. RESULTS: A total of 10 studies (three randomized-controlled trials and seven nonrandomized studies) were included. Of the six preoperative studies, five reported that hemoglobin was significantly higher in the intravenous group compared with oral iron/observation. Among the four postoperative studies, three studies suggested that hemoglobin was significantly higher in the intravenous group compared with oral iron/observation. The overall risk of bias for all randomized-controlled trials was low. Quality assessments for nonrandomized studies found the risk of bias to be moderate for four studies and critical for three studies. CONCLUSION: Despite the limitations of the current body of evidence, there is a likely benefit to the use of intravenous iron in this patient population. Further confirmatory research is needed to draw empirical conclusions.

Serial Measurements of Left Ventricular Systolic and Diastolic Function by Cardiac Magnetic Resonance Imaging in Patients with Early Stage Breast Cancer on Trastuzumab.

Our aim was to evaluate the temporal changes in left ventricular (LV) diastolic filling in relation to other LV parameters using cardiac MRI (CMR) in patients with HER2 positive breast cancer receiving trastuzumab therapy. Fourty-one women with early stage HER2+ breast cancer underwent serial CMR (baseline, 6, 12, and 18 months) after initiation of trastuzumab therapy. A single, blinded observer measured LV parameters on de-identified CMRs in random order. Linear mixed models were used to investigate temporal changes. Compared to baseline, there were significant decreases in systolic function as measured by both left ventricular ejection fraction (LVEF) (p <0.001 at 6 and 12 months) and peak ejection rate corrected for end-diastolic volume (PER/LVEDV) (p = 0.008 at 6 months, p = 0.01 at 12 months). However, these differences were no longer significant at 18 months. In contrast, significant reductions in diastolic function as measured by LV peak filling rate corrected for end-diastolic volume (PFR/LVEDV) were observed at 6 months (p = 0.012), 12 months (p = 0.031), and up to 18 months (p = 0.034). There were no significant temporal changes in the time to peak filling rate corrected for cardiac cycle (TPF/RR). The reduction in PFR/LVEDV at 18 months was no longer significant when corrected for heart rate. In conclusion, there were significant subclinical deleterious effects on both LV systolic and diastolic function among patients receiving trastuzumab. While there was recovery in LV systolic function after therapy cessation at 18 months, reduction in PFR/LVEDV appeared to persist. Thus, diastolic dysfunction may serve as a marker of trastuzumab-induced cardiotoxicity that needs to be confirmed in a larger study.

Early diastolic strain rate measurements by cardiac MRI in breast cancer patients treated with trastuzumab: a longitudinal study.

We evaluated temporal changes in early diastolic strain rates by cardiovascular magnetic resonance (CMR) as an early detector of trastuzumab-induced ventricular dysfunction. We conducted a prospective, multi-centre, longitudinal observational study of 41 trastuzumab-treated breast cancer women who underwent serial CMR (baseline, 6, 12, and 18 months). Two blinded readers independently measured left ventricular ejection fraction (LVEF), peak systolic strain parameters (global longitudinal strain [GLS] and global circumferential strain [GCS]), and early diastolic strain rate parameters (global longitudinal diastolic strain rate [GLSR-E], global circumferential diastolic strain rate [GCSR-E], and global radial diastolic strain rate [GRSR-E]), by feature tracking (FT-CMR) using CMR42. There was a significant decline in peak systolic strain GLS and GCS at 6 months (p = 0.024 and p < 0.001, respectively) and 12 months (p = 0.002 and p < 0.001, respectively), followed by recovery at 18 months, which paralleled decline in LVEF at 6 months (p = 0.034) and 12 months (p = 0.012). Conversely, early diastolic strain rates GLSR-E and GCSR-E did not significantly change over 18 months (p > 0.10), while GRSR-E was marginally significant at 12 months (p = 0.021). There was no significant correlation between changes at 6 months in LVEF and GLSR-E or GRSR-E (p > 0.10), and a marginally significant weak correlation between LVEF and GCSR-E (p = 0.046). Among trastuzumab-treated patients without overt cardiotoxicity, there was no consistent temporal change in FT-CMR-derived diastolic strain rate parameters up to 18 months, in contrast to decline in systolic strain and LVEF. Systolic strains by FT-CMR are likely more useful than diastolic strain rates for monitoring subclinical trastuzumab-related myocardial dysfunction.ClinicalTrials.gov identifier NCT01022086.

Myocardial strain imaging by cardiac magnetic resonance for detection of subclinical myocardial dysfunction in breast cancer patients receiving trastuzumab and chemotherapy.

BACKGROUND: Our objectives were to evaluate the temporal changes in CMR-based strain imaging, and examine their relationship with left ventricular ejection fraction (LVEF), in patients treated with trastuzumab. PATIENTS AND METHODS: In this prospective longitudinal observational study, 41 women with HER2+ breast cancer treated with chemotherapy underwent serial CMR (baseline, 6, 12, and 18 months) after initiation of trastuzumab (treatment duration 12 months). LVEF and LV strain (global longitudinal[GLS] and circumferential[GCS]) measurements were independently measured by 2 blinded readers. RESULTS: Of the 41 patients, 56% received anthracycline-based chemotherapy. Compared to baseline (60.4%, 95%CI 59.2-61.7%), there was a small but significant reduction in LVEF at 6 months (58.4%, 95%CI 56.7-60.0%, p = 0.034) and 12 months (57.9%, 95%CI 56.4-59.7%, p = 0.012), but not at 18 months (60.2%, 95%CI 58.2-62.2%, p = 0.93). Similarly, compared to baseline, GLS and GCS decreased significantly at 6 months (p = 0.024 and < 0.001, respectively) and 12 months (p = 0.002 and < 0.001, respectively) with an increase in LV end-diastolic volume, but not at 18 months. There were significant correlations between the temporal (6 month-baseline) changes in LVEF, and all global strain measurements (Pearson's r = -0.60 and r = -0.75 for GLS and GCS, respectively, all p < 0.001). CONCLUSION: There was a significant reduction in LV strain during trastuzumab treatment, which correlated with a concurrent subtle decline in LVEF and was associated with an increase in LV end-diastolic volume. LV strain assessment by CMR may be a promising method to monitor for subclinical myocardial dysfunction in breast cancer patients receiving chemotherapy. Future studies are needed to determine its prognostic and therapeutic implications.

Longitudinal assessment of right ventricular structure and function by cardiovascular magnetic resonance in breast cancer patients treated with trastuzumab: a prospective observational study.

BACKGROUND: There are limited data on the effects of trastuzumab on the right ventricle (RV). Therefore, we sought to evaluate the temporal changes in right ventricular (RV) structure and function as measured by cardiovascular magnetic resonance (CMR), and their relationship with left ventricular (LV) structure and function in breast cancer patients treated with trastuzumab. METHODS: Prospective, longitudinal, observational study involving 41 women with HER2+ breast cancer who underwent serial CMR at baseline, 6, 12, and 18 months after initiation of trastuzumab. A single blinded observer measured RV parameters on de-identified CMRs in a random order. Linear mixed models were used to investigate temporal changes in RV parameters. RESULTS: Of the 41 women (age 52 ± 11 years), only one patient experienced trastuzumab-induced cardiotoxicity. Compared to baseline, there were small but significant increases in the RV end-diastolic volume at 6 months (p = 0.002) and RV end-systolic volume at 6 and 12 months (p < 0.001 for both), but not at 18 months (p = 0.82 and 0.13 respectively). RV ejection fraction (RVEF), when compared to baseline (58.3%, 95% CI 57.1-59.5%), showed corresponding decreases at 6 months (53.9%, 95% CI 52.5-55.4%, p < 0.001) and 12 months (55%, 95% CI 53.8-56.2%, p < 0.001) that recovered at 18 months (56.6%, 95% CI 55.1-58.0%, p = 0.08). Although the temporal pattern of changes in LVEF and RVEF were similar, there was no significant correlation between RVEF and LVEF at baseline (r = 0.29, p = 0.07) or between their changes at 6 months (r = 0.24, p = 0.17). CONCLUSION: In patients receiving trastuzumab without overt cardiotoxicity, there is a subtle but significant deleterious effect on RV structure and function that recover at 18 months, which can be detected by CMR. Furthermore, monitoring of LVEF alone may not be sufficient in detecting early RV injury. These novel findings provide further support for CMR in monitoring early cardiotoxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01022086 . Date of registration: November 27, 2009.

Pilot study of the endothelin-A receptor selective antagonist BMS-193884 for the treatment of erectile dysfunction.

Endothelins have been postulated to be important regulators of penile erectile function. The endothelin-A receptor antagonist BMS-193884 was evaluated as a treatment for mild-to-moderate erectile dysfunction in an animal model and in human volunteer subjects. In laboratory studies, organ bath preparations of rabbit and human penile cavernosal tissue strips were incubated with BMS-193884 and exposed to increasing concentrations of endothelins. In rabbit tissue, 1 microM BMS-193884 significantly inhibited contraction to ET-1, ET-2, and ET-3 by 34.5%, 42.9%, and 100%, respectively. In human tissue, 1 microM BMS-193884 inhibited contraction to ET-2 by 44.4%. In rabbit tissue strips contracted with 20 nM of ET-1 or ET-2, BMS-1 93884 caused dose-dependent relaxation with EC50 values of 107.2 +/- 32.3 nM and 1.7 +/- 0.5 nM, respectively. In anesthetized male rabbits, intravenous administration of BMS-193884 (systemic plasma concentration approximately 50 and 100 nM) increased the duration of pelvic nerve-stimulated penile erection. To further assess the safety and efficacy of BMS-193884, 53 men diagnosed with mild-to-moderate erectile dysfunction were administered oral placebo or 100 mg BMS-193884 in a double-blind fashion. Evaluations were based on 1) erectile function testing during 2 in-office visits and 2) diary and questionnaire data of 4 intercourse attempts over 2-4 weeks of home use. Although the drug was well tolerated, BMS-193884 did not significantly improve erectile function during office visits or home use when compared to placebo. Thus, BMS-193884 facilitated cavernosal smooth muscle relaxation ex vivo and prolonged penile tumescence in vivo. In contrast, a pilot clinical study failed to show enhancement of erectile response in men with mild-to-moderate erectile dysfunction. The disparity between the laboratory and clinical studies suggests that there may be differences between species with regard to the role of endothelin in erectile function.