841 research outputs found
Chemotherapy following radium-223 dichloride treatment in ALSYMPCA
BACKGROUND
Radium-223 prolongs overall survival in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases, regardless of prior docetaxel. Whether or not chemotherapy can be safely administered following radium-223 treatment is of clinical importance. An exploratory analysis of prospectively collected data, from the ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) patient subgroup who received chemotherapy after radium-223 or placebo treatment, was conducted to evaluate the safety and efficacy of chemotherapy following radium-223.
METHODS
In ALSYMPCA, CRPC patients with symptomatic bone metastases and no visceral metastases were randomized 2:1 to receive six injections of radium-223 (50 kBq/kg IV) or placebo plus best standard of care, stratified by prior docetaxel, baseline alkaline phosphatase, and current bisphosphonate use. In this exploratory analysis, chemotherapy agents administered following study treatment were identified; timing and duration were calculated. Hematologic safety was reviewed, and overall survival analyzed.
RESULTS
Overall, 142 radium-223 and 64 placebo patients received subsequent chemotherapy; most common were docetaxel (70% radium-223, 72% placebo) and mitoxantrone (16% radium-223, 20% placebo). The majority of patients (61% radium-223, 58% placebo) had received prior docetaxel. Radium-223 patients started subsequent chemotherapy later than placebo patients; chemotherapy duration was similar between groups. In radium-223 and placebo patients receiving subsequent chemotherapy, median hematologic values (hemoglobin, neutrophils, and platelets) remained nearly constant up to 18 months following start of chemotherapy, regardless of prior docetaxel treatment. A low percentage of patients in both groups had grades 3â4 hematologic values (<10%). Platelet count decline, from last measurement before chemotherapy, was numerically greater in radium-223 versus placebo patients. Median overall survivals from start of chemotherapy were 16.0 and 15.8 months following radium-223 and placebo, respectively.
CONCLUSIONS
Chemotherapy following radium-223, regardless of prior docetaxel, is feasible and appears to be well tolerated in patients with CRPC and symptomatic bone metastases
Advances in targeted Alpha therapy for prostate cancer
BACKGROUND: Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. DESIGN: In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. RESULTS: A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor (AR)-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. CONCLUSIONS: The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment
Is the abundance of Faecalibacterium prausnitzii relevant to Crohn's disease?
Reports that bacteria within the Firmicutes phylum, especially the species Faecalibacterium prausnitzii, are less abundant in Crohnâs disease (CD) patients and supernatants from cultures of this bacterium are anti-inflammatory prompted the investigation of the possible correlations between the abundance of F.prausnitzii and the response to treatment in patients with gut diseases and healthy controls. In a randomized, double-blind trial, faeces were collected from healthy volunteers, and from patients with active CD, ulcerative colitis (UC) and irritable bowel syndrome before and after treatment. The levels of F. prausnitzii DNA in faecal suspensions were determined by PCR. Treatment by an elemental diet was effective, resulting in decreases in both the Harvey and Bradshaw index (P<0.001) and the concentrations of serum C-reactive protein (P<0.05). The total levels of F. prausnitzii in faecal samples from CD patients at presentation were lower than those in the other groups both before and after the treatment. There was no correlation between F. prausnitzii abundance and the severity of CD before treatment. Clinical improvement unexpectedly correlated with a significant decrease in the abundance of F. prausnitzii, especially the A2-165 subgroup (P<0.05). Our data suggest that a paucity of F. prausnitzii in the gastrointestinal microbial communities is likely to be a minor aetiological factor in CD: recovery following elemental diet is attributed to lower levels of gut flora
Influence of Crohnâs disease related polymorphisms in innate immune function on ileal microbiome
We have previously identified NOD2 genotype and inflammatory bowel diseases (IBD) phenotype, as associated with shifts in the ileal microbiome (âdysbiosisâ) in a patient cohort. Here we report an integrative analysis of an expanded number of Crohn's disease (CD) related genetic defects in innate immune function (NOD2, ATG16L1, IRGM, CARD9, XBP1, ORMDL3) and composition of the ileal microbiome by combining the initial patient cohort (Batch 1, 2005â2010, n = 165) with a second consecutive patient cohort (Batch 2, 2010â2012, n = 118). These combined patient cohorts were composed of three non-overlapping phenotypes: 1.) 106 ileal CD subjects undergoing initial ileocolic resection for diseased ileum, 2.) 88 IBD colitis subjects without ileal disease (predominantly ulcerative colitis but also Crohnâs colitis and indeterminate colitis, and 3.) 89 non-IBD subjects. Significant differences (FDR C. difficile infection, and NOD2 genotype on ileal dysbiosis in the expanded analysis. The relative abundance of the Proteobacteria phylum was positively associated with ileal CD and colitis phenotypes, but negatively associated with NOD2R genotype. Additional associations with ORMDL3 and XBP1 were detected at the phylum/subphylum level. IBD medications, such as immunomodulators and anti-TNFα agents, may have a beneficial effect on reversing dysbiosis associated with the IBD phenotype. Exploratory analysis comparing microbial composition of the disease unaffected region of the resected ileum between 27 ileal CD patients who subsequently developed endoscopic recurrence within 6â12 months versus 34 patients who did not, suggested that microbial biomarkers in the resected specimen helped stratify patients with respect to risk of post-surgical recurrence.</div
Efficacy and Safety of Radium-223 Dichloride in Symptomatic Castration-resistant Prostate Cancer Patients With or Without Baseline Opioid Use From the Phase 3 ALSYMPCA Trial
Background: The phase 3 ALSYMPCA trial enrolled metastatic castration-resistant prostate
cancer patients with or without baseline opioid use.
Objective: To assess the efficacy and safety of radium-223 dichloride (radium-223) versus
placebo in ALSYMPCA patients by baseline opioid use.
Design, setting, and participants: Nine hundred and twenty one patients enrolled at 136 centers
globally.
Intervention: Radium-223 (50 kBq/kg, intravenous injection) every 4 wk for six cycles or
matching placebo, each plus best standard of care.
Outcome measurements and statistical analysis: Primary endpoint (overall survival [OS]),
main secondary efficacy endpoints, and safety were evaluated by baseline opioid use.
Additional analyses included time to first opioid use, time to first external beam radiation
therapy for bone pain, and safety of concomitant external beam radiation therapy.
Results and limitations: At baseline, 408 (44%) patients had no pain and no analgesic use or
mild pain with nonopioid therapy (World Health Organization ladder pain score 0â1 [nonopioid
subgroup]), and 513 (56%) had moderate pain with occasional opioids or severe pain
with regular daily opioids (World Health Organization ladder pain score 2â3 [opioid subgroup]).
Radium-223 significantly prolonged OS versus placebo in nonopioid (hazard ratio
[HR] = 0.70; 95% confidence interval [CI]: 0.52â0.93; p = 0.013) and opioid (HR = 0.68; 95% CI:
0.54â0.86; p = 0.001) subgroups, and significantly reduced risk of symptomatic skeletal events
versus placebo, regardless of baseline opioid use (nonopioid subgroup: HR = 0.56, 95% CI: 0.39â
0.82, p = 0.002; opioid subgroup: HR = 0.72, 95% CI: 0.53â0.98, p = 0.038). Time to first opioid
use for bone pain was significantly delayed with radium-223 versus placebo (HR = 0.62, 95% CI:
0.46â0.85, p = 0.002). Adverse event incidences were similar between opioid subgroups.
Conclusions: Radium-223 versus placebo significantly prolonged OS and reduced symptomatic
skeletal event risk with a favorable safety profile in castration-resistant prostate cancer
patients with symptomatic bone metastases, regardless of baseline opioid use.
Patient summary: In this ALSYMPCA opioid subgroup analysis, baseline symptom levels did
not appear to impact radium-223 dichloride efficacy or safet
Prioritizing conservation areas to mitigate connectivity loss and local extinction risk of a small carnivore (Leopardus guttulus) in South America
Effective conservation management depends on the maintenance of key areas that allow population connectivity across the landscape. However, the lack of knowledge of how habitat conversion affects species movement hinders the identification of these areas. Here, we analyzed the impact of habitat fragmentation on landscape connectivity for Leopardus guttulus, a small Neotropical felid threatened by the high habitat fragmentation across the Atlantic Forest, and mapped and ranked the most important core areas and corridors for conservation actions. We also estimated genetic diversity indices and predicted the viability of the current core areas in the future. Our analyses suggest that L. guttulus populations are fragmented, and connectivity links between populations are few and weak. We predict that due to their size, estimated density and low connectivity, some current core areas may not maintain viable populations in the long-term. Also, ongoing land-use changes may further isolate remaining populations, leading to progressive reductions in the populations they support. In this study, we spatially prioritize the most critical areas for L. guttulus conservation and highlighted the urge that exists in the adoption of management measures for its conservation
Gut microbiota induce IGF-1 and promote bone formation and growth
New interventions are needed to improve bone health and reduce the risk for osteoporosis and fracture. Dysbiosis is increasingly linked to metabolic abnormalities, although the effect of the microbiota on skeletal health is poorly understood. Previous studies suggest microbiota are detrimental to bone by increasing resorption. In this report, we show that the gut resident microbiota promote bone formation, as well as resorption, with long-term exposure to microbiota resulting in net skeletal growth. Microbiota induce the hormone insulin-like growth factor 1 (IGF-1), which promotes bone growth and remodeling. Short-chain fatty acids (SCFAs), produced when microbiota ferment fiber, also induce IGF-1, suggesting a mechanism by which microbiota affect bone health. Manipulating the microbiome or its metabolites may afford opportunities to optimize bone health and growth
Prospects for Radiopharmaceuticals as Effective and Safe Therapeutics in Oncology and Challenges of Tumor Resistance to Radiotherapy
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