Small cell lung cancer (SCLC) is a common lung cancer which presents with extensive stage disease at time of diagnosis in two-thirds of patients. For treatment of advanced disease, traditional ...platinum doublet chemotherapy induces response rates up to 80% but with few durable responses. CPI-613 is a novel anti-cancer agent that selectively inhibits the altered form of mitochondrial energy metabolism in tumor cells.
We evaluated CPI-613 with a single-arm, open-label phase II study in patients with relapsed or refractory SCLC. CPI-613 was given at a dose of 3,000 mg/m2 on days 1 and 4 of weeks 1-3 of 4 week cycle. The primary outcome was response rate as assessed by CT imaging using RECIST v1.1 criteria. Secondary outcomes were progression-free survival (PFS), overall survival (OS), and toxicity. Twelve patients were accrued (median age 57yo) who had previously received between 1 and 4 lines of chemotherapy (median 1) for SCLC with a treatment-free interval of less than 60 days in 9 of the 12 patients.
No complete or partial responses were seen. Ten patients (83%) progressed as best response and 2 (17%) were not evaluable for response. Median time to progression was 1.7 months (range 0.7 to 1.8 months). Eleven patients (92%) died with median overall survival of 4.3 months (range 1.2 to 18.2 months). The study was closed early due to lack of efficacy. Of note, three out of three patients who progressed after CPI-613 and were subsequently treated with standard topotecan then demonstrated treatment response with survival for 18.2, 7.4, and 5.1 months. We conducted laboratory studies which found synergy in-vitro for CPI-613 with topotecan.
Single agent CPI-613 had no efficacy in this study. Further study of CPI 613 in combination with a topoisomerase inhibitor is warranted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract We sought to determine the frequency by which decreases in left ventricular (LV) end-diastolic volume (LVEDV) with and without increases in end-systolic volume (LVESV) influenced early ...cancer treatment-associated declines in left ventricular ejection fraction (LVEF) or LV mass. One hundred and twelve consecutively recruited individuals (aged 52 ± 14 years) with cancer underwent blinded cardiovascular magnetic resonance (CMR) measures of LV volumes, mass, and LVEF before and 3 months after initiating potentially cardiotoxic chemotherapy (72 % of participants received anthracyclines). Twenty-six participants developed important declines in LVEF of >10% or to values <50% at 3 months, in whom 19% versus 60%, respectively, experienced their decline in LVEF due to isolated declines in LVEDV versus an increase in LVESV; participants who dropped their LVEF due to decreases in LVEDV lost more LV mass than those who dropped their LVEF due to an increase in LVESV ( p =0.03). Nearly a fifth of individuals experience marked LVEF declines due to an isolated decline in LVEDV after initiating potentially cardiotoxic chemotherapy. Since reductions in intravascular volume (which could be treated by volume repletion) may account for LVEDV related declines in LVEF, these data indicate that LV volumes should be reviewed along with LVEF when acquiring imaging studies for cardiotoxicity during treatment for cancer.
Background Although changes in left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume, and global circumferential strain occur during cancer treatment, the relationship ...of these changes to the 2-year post-cancer-treatment measures of left ventricular ejection fraction (LVEF) are unknown. Methods and Results In a prospective, continuously recruited cohort of 95 patients scheduled to receive potentially cardiotoxic chemotherapy for breast cancer, lymphoma, or soft tissue sarcoma, measures of left ventricular end-diastolic volume, LVESV, global circumferential strain, and LVEF were acquired via cardiac magnetic resonance imaging before and then 3 and 24 months after initiating treatment by individuals blinded to all patient identifiers. Participants had an average age of 54±15 years; 68% were women, and 82% were of white race. LVEF declined from 62±7% to 58±9% over the 24 months (
<0.0001), with 42% of participants experiencing a >5% decline in LVEF at 24 months. Predictors of a 24-month >5% decline in LVEF included the following factors from baseline to 3 months into treatment: (1) >3-mL increases in LVESV (
=0.033), (2) >3-mL increases in LVESV or 10-mL declines in left ventricular end-diastolic volume with little change in LVESV (
=0.001), or (3) ≥10% deteriorations in global circumferential strain with little change in LVESV (
=0.036). Conclusion During receipt of potentially cardiotoxic chemotherapy, increases in LVESV, the absence of its deterioration during decreases of left ventricular end-diastolic volume, or the deterioration of global circumferential strain without a marked decrease in LVESV help identify those who will develop more permanent 2-year declines in LVEF.
High-dose glucocorticoids such as prednisone are combined with cytotoxic chemotherapy in the R-CHOP or dose adjusted R-EPOCH regimens used for non-Hodgkin lymphoma (NHL). In this retrospective study, ...our primary objective was to evaluate the incidence of hyperglycemia during first-line R-CHOP or DA-EPOCH-R. The secondary objectives were to evaluate the incidence of chemotherapy alteration and overall survival in those with and without hyperglycemia. One hundred and sixty patients were eligible. We found that 47% of all patients had at least one hyperglycemic episode and hyperglycemia was associated with chemotherapy alteration (p = .028). Multivariate analysis revealed international prognostic index (IPI) ≥ 3 (p = .045) and chemotherapy alteration (p = .001) were associated with decreased overall survival. We conclude that hyperglycemia is common during first-line NHL treatment with R-CHOP or DA-EPOCH-R, even in the absence of known diabetes and is associated with alterations of chemotherapy. Baseline pre-PET scan fasting blood glucose of 100 mg/dL or higher may predict hyperglycemia during therapy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Purpose
To investigate the impact of hyperglycemia and glycemic variability during intensive acute myeloid leukemia therapy (AML) on outcomes by age.
Methods
Retrospective study of 262 consecutive ...patients with newly diagnosed AML hospitalized for intensive induction. Hyperglycemia was assessed by mean blood glucose (BG) (mg/dL) during hospitalization and glycemic variability was determined by the standard deviation (SD) of mean BG. Outcomes were complete remission ± incomplete count recovery (CR + CRi), and overall survival (OS). We used logistic regression to evaluate CR + CRi, and Cox proportional hazard models for OS, stratified by age (< 60 vs ≥ 60 years).
Results
Older patients (
N
= 138, median age 70) had higher baseline comorbidity (CCI > 1 60.1% vs 25.8%) and prevalence of diabetes (20.3% vs 7.3%) compared to younger (
N
= 124, median age 47). The mean ± SD number of BG values obtained per patient during hospitalization was 61 ± 71. The mean (± SD) glucose (mg/dL) during hospitalization was 121.7 (25.9) in older patients (≥ 60 years) versus 111.6 (16.4) in younger. In older patients, higher mean glucose and greater glycemic variability were associated with lower odds of remission (OR 0.80, 95% CI 0.69–0.93 and OR 0.73, 95% CI 0.61–0.88 respectively, per 10-unit increase) and higher mortality rates (HR 1.13, 95% CI 1.05–1.21 and HR 1.17, 95% CI 1.09–1.26, respectively, per 10-unit increase) in multivariate analyses.
Conclusions
Our observations that hyperglycemia and increased glycemic variability were associated with lower remission rates and increased mortality in older patients suggest glycemic control may be a potentially modifiable factor to improve AML outcomes.
The presence, within the human bone marrow, of cells with both endothelial and hemogenic potential has been controversial. Herein, we identify, within the human fetal bone marrow, prior to ...establishment of hematopoiesis, a unique APLNR+, Stro-1+ cell population, co-expressing markers of early mesodermal precursors and/or hemogenic endothelium. In adult marrow, cells expressing similar markers are also found, but at very low frequency. These adult-derived cells can be extensively culture expanded in vitro without loss of potential, they preserve a biased hemogenic transcriptional profile, and, upon in vitro induction with OCT4, assume a hematopoietic phenotype. In vivo, these cells, upon transplantation into a fetal microenvironment, contribute to the vasculature, and generate hematopoietic cells that provide multilineage repopulation upon serial transplantation. The identification of this human somatic cell population provides novel insights into human ontogenetic hematovascular potential, which could lead to a better understanding of, and new target therapies for, malignant and nonmalignant hematologic disorders.
Myocardial injury because of oxidative stress manifesting through reductions in left ventricular ejection fraction (LVEF) may occur after the administration of anthracycline-based chemotherapy ...(A-bC). We hypothesized that bilirubin, an effective endogenous antioxidant, may attenuate the reduction in LVEF that sometimes occurs after receipt of A-bC. We identified 751 consecutively treated patients with cancer who underwent a pre-A-bC LVEF measurement, exhibited a serum total bilirubin level <2 mg/dl, and then received a post-A-bC LVEF assessment because of symptomatology associated with heart failure. Analysis of variance, Tukey's Studentized range test, and chi-square tests were used to evaluate an association between bilirubin and LVEF changes. The LVEF decreased by 10.7 ± 13.7%, 8.9 ± 11.8%, and 7.7 ± 11.5% in group 1 (bilirubin at baseline ≤0.5 mg/dl), group 2 (bilirubin 0.6 to 0.8 mg/dl), and group 3 (bilirubin 0.9 to 1.9 mg/dl), respectively. More group 1 patients experienced >15% decrease in LVEF compared with those in group 3 (p = 0.039). After adjusting for age, coronary artery disease/myocardial infarction, diabetes mellitus, hematocrit, and the use of cardioactive medications, higher precancer treatment bilirubin levels and lesser total anthracycline doses were associated with LVEF preservation (p = 0.047 and 0.011, respectively). In patients treated with anthracyclines who subsequently develop symptoms associated with heart failure, pre-anthracycline treatment serum bilirubin levels inversely correlate with subsequent deterioration in post-cancer treatment LVEF. In conclusion, these results suggest that increased levels of circulating serum total bilirubin, an intrinsic antioxidant, may facilitate preservation of LVEF in patients receiving A-bC for cancer.
Objectives
Prior studies have identified a relationship between body mass index (BMI) and intraperitoneal (IP) fat with heart failure; however, in prior studies of cancer patients receiving ...potentially cardiotoxic chemotherapy, elevations in BMI have not necessarily been associated with decrements in heart function. This study tested the hypothesis that IP fat may be associated with left ventricular ejection fraction (LVEF) decline among cancer patients receiving potentially cardiotoxic chemotherapy.
Methods
In this prospective study of 61 cancer patients (23 breast cancer, 32 lymphoma, and 6 sarcoma), IP fat and other assessments of body composition, and changes in LVEF from pre‐ to postcancer treatment using noninvasive magnetic resonance imaging was ascertained.
Results
After accounting for age, baseline LVEF, and confounding variables, pre‐ to 24‐month post‐treatment LVEF changes were inversely correlated with IP fat (r = −0.33; p = 0.02) and positively correlated with measures of subcutaneous (SQ) fat (r = 0.33; p = 0.01). These LVEF changes were not correlated with BMI (r = 0.12; p = 0.37).
Conclusion
Among patients receiving potentially cardiotoxic chemotherapy, pretreatment IP fat was associated with subsequent declines in LVEF. There was no association between BMI and LVEF decline. These findings may be related to a potential protective effect of SQ fat.
Key Clinical Message
We report a 53‐year‐old man diagnosed with Richter syndrome. He was heavily pretreated and was refractory to prior therapy. He received rituximab and ibrutinib, and achieved a ...significant response after 1 month of therapy. Our case illustrates the importance of investigation of rituximab and ibrutinib in Richter's syndrome.
We report a 53‐year‐old man diagnosed with Richter syndrome. He was heavily pretreated and was refractory to prior therapy. He received rituximab and ibrutinib, and achieved a significant response after 1 month of therapy. Our case illustrates the importance of investigation of rituximab and ibrutinib in Richter's syndrome.
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