Inherited DNA-repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood.
To investigate the ...clinical significance of germline DNA-repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving next-generation hormonal therapy (NHT), with a particular emphasis on BRCA/ATM mutations.
We interrogated 50 genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT with abiraterone or enzalutamide.
We assessed the impact of germline DNA-repair gene mutation status on ≥50% and ≥90% PSA responses, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Survival outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses.
Among 172 mCRPC patients included, germline mutations (in any DNA-repair gene) were found in 12% (22/172) of men, and germline BRCA/ATM mutations specifically in 5% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs no mutations) with respect to PSA-PFS (hazard ratio HR 0.47; p=0.061), PFS (HR 0.50; p=0.090), and OS (HR 0.28; p=0.059). In propensity score-weighted multivariable analyses, outcomes were superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95% confidence interval CI 0.25–0.92; p=0.027), PFS (HR 0.52, 95% CI 0.28–0.98; p=0.044), and OS (HR 0.34, 95% CI 0.12–0.99; p=0.048), but not in men with non-BRCA/ATM germline mutations (all p>0.10). These results require prospective validation, and our conclusions are limited by the small number of patients (n=9) with BRCA/ATM mutations.
Outcomes to first-line NHT appear better in mCRPC patients harboring germline BRCA/ATM mutations (vs no mutations), but not for patients with other non-BRCA/ATM germline mutations.
Patients with metastatic castration-resistant prostate cancer and harboring germline mutations in BRCA1/2 and ATM benefit from treatment with abiraterone and enzalutamide.
To determine whether and how germline DNA-repair gene mutations influence clinical outcomes to abiraterone or enzalutamide in patients with castration-resistant prostate cancer (CRPC), we performed germline genotyping for 50 DNA-repair genes using blood samples from 172 patients with CRPC beginning first-line systemic therapy with abiraterone or enzalutamide. We discovered that the presence of germline DNA-repair gene defects (particularly mutations in the BRCA1/2 and ATM genes) were associated with better outcomes to abiraterone and enzalutamide.
Background
Prostate‐specific membrane antigen (PSMA) is a rational target for noninvasive detection of recurrent prostate cancer (PCa) and for therapy of metastatic castration‐resistant prostate ...cancer (mCRPC) with PSMA‐targeted agents. Here we conducted serial measurements of PSMA expression on circulating tumor cells (CTCs) to evaluate patterns of longitudinal PSMA dynamics over the course of multiple sequential therapies.
Methods
A retrospective investigation of men with mCRPC undergoing evaluation at medical oncology clinics at our institution assessed the dynamics of PSMA expression in the context of different systemic treatments administered sequentially. Eligibility included patients who began systemic therapies with androgen receptor (AR)‐directed agents or taxane agents for whom peripheral blood samples were tested for CTC mRNA of AR splice variant‐7 (AR‐V7), prostate‐specific antigen (PSA), and PSMA (with >2 CTC + results) in a CLIA‐accredited laboratory.
Results
From August 2015 to November 2017, we identified 96 eligible men. Fifteen had greater than or equal to 2 sequential therapies and evaluable CTC samples, greater than or equal to 1 expressing PSMA (PSMA+). Among the 15 patients included in this analysis, a total of 54 PSMA status evaluations were performed in the context of 48 therapies during a median follow‐up of 18 months. At baseline, PSMA signal was detected (“positive”) in 11 of 15 (73.3%) patients, while for 4 of 15 (26.7%) patients PSMA signal was undetectable (“negative”). In all but two patients, the baseline collection corresponded with a change in treatment. On the second assessment, PSMA increases were detected in all 4/4 (100%) PSMA‐negative patients and 8 of 11 (72.7%) PSMA‐positive patients. PSMA significantly decreased in a patient treated with 177Lu‐PSMA‐617. Serum PSA declines were seen in 7 of 8 (88%) of the treatment periods where PSMA decreased.
Conclusions
PSMA expression in CTCs is a dynamic marker. PSMA transcript declines appear to be associated with concurrent decreases in serum PSA. Sequential CTC sampling could provide a noninvasive response assessment to systemic treatment for mCRPC.
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Background: Inherited DNA repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully ...understood. Here we investigated the clinical significance of germline DNA repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line novel hormonal therapy (NHT), with a particular emphasis on BRCA1/2 and ATM mutations. Methods: We interrogated 50 DNA repair genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT: abiraterone or enzalutamide. We assessed the impact of germline DNA repair gene mutation status on ≥50% and ≥90% PSA response rates, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses. Results: Among 172 mCRPC patients, germline mutations (in any DNA repair gene) were found in 12.8% (22/172) of men, and germline BRCA/ATM mutations were found in 5.2% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs. no mutations) with respect to ≥90% PSA responses (78% vs. 28%, P = 0.004), PSA-PFS (HR 0.47, P = 0.061), PFS (HR 0.50, P = 0.090) and OS (HR 0.28, P = 0.059). In propensity score-weighted multivariable analyses, outcomes remained superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95%CI 0.25–0.92, P = 0.027), PFS (HR 0.52, 95%CI 0.28–0.98, P = 0.044) and OS (HR 0.34, 95%CI 0.12–0.99, P = 0.048), but this was not true for men with non- BRCA/ATM germline mutations (all endpoints, P > 0.10). Conclusions: Outcomes to first line NHT appeared better in mCRPC patients harboring germline BRCA/ATM mutations (vs. no mutations), but not for patients with other non- BRCA/ATM germline mutations. These results support the hypothesis that AR may promote DNA repair, and that inhibiting AR in the context of homologous recombination deficiency may lead to synthetic lethality.
IMPORTANCE: Randomized clinical trials (RCTs) and meta-analyses of sublingual immunotherapy (SLIT) for the treatment of seasonal allergic rhinoconjunctivitis (SARC) have shown a modest clinical ...benefit compared with placebo. Furthermore, indirect comparison by meta-analyses showed that subcutaneous immunotherapy is more effective than SLIT. Despite these data, SLIT has become the most prescribed treatment of SARC in Europe in recent years, and it was approved by the US Food and Drug Administration for the treatment of SARC to grass pollen in the United States on April 1, 2014. OBJECTIVE: To assess the efficacy and safety of the grass pollen sublingual tablets licensed as drugs in the treatment of patients with SARC to grass pollen. DATA SOURCES: Computerized bibliographic searches of MEDLINE, EMBASE, the Cochrane Library, and ClinicalTrials.gov (from inception to April 30, 2014) were supplemented with a manual search of reference lists. STUDY SELECTION: Randomized clinical trials were included if they compared the grass pollen SLIT tablets approved by regulatory authorities in the European Union and the United States for SARC with placebo. DATA EXTRACTION AND SYNTHESIS: Data on populations, interventions, and outcomes were extracted from each RCT according to the intent-to-treat method by 2 independent observers and were combined using the method by DerSimonian and Laird. MAIN OUTCOMES AND MEASURES: The primary end point was the difference in the symptom score and medication score between SLIT and placebo. We pooled data using random-effects meta-analysis, with standardized mean differences (SMDs) and 95% CIs reported. RESULTS: Data were available in 13 RCTs for the symptom score (4659 patients) and in 12 RCTs for the medication score (4558 patients). We found a small treatment benefit in the symptom score (SMD, −0.28; 95% CI, −0.37 to −0.19; P < .001) and in the medication score (SMD, −0.24; 95% CI, −0.31 to −0.17; P < .001). Adverse events were reported in 1384 of 2259 patients (61.3%) receiving SLIT and in 477 of 2279 patients (20.9%) receiving placebo. Seven patients in the SLIT group reported treatment-related adverse events requiring epinephrine. CONCLUSIONS AND RELEVANCE: Findings show a small benefit of the grass pollen sublingual tablets in reducing symptoms and in decreasing the use of symptomatic medication (antihistamines and corticosteroids) in patients with SARC. Considering the low magnitude of the benefit, the convenience and easy administration do not seem to be sufficient reasons for the choice of SLIT.
Background Subcutaneous (SCIT) and sublingual (SLIT) immunotherapy are the 2 most prescribed routes for administering allergen-specific immunotherapy. They were shown to be effective in control of ...symptoms and in reducing rescue medication use in patients with allergic diseases, but their effectiveness has to be balanced against side effects. In recent years, SLIT has been increasingly prescribed, instead of SCIT, because of improved safety and easy administration. Objective We assessed which route is the most effective in the treatment of patients with seasonal allergic rhinitis to grass pollen. Methods An indirect meta-analysis–based comparison between SCIT and SLIT was performed. Treatment efficacy was determined as the standardized mean difference (SMD) in symptom and medication scores obtained with active treatment, SCIT or SLIT, compared with placebo. Studies were included if they were double-blind randomized controlled trials comparing SCIT or SLIT with placebo. Thirty-six randomized controlled trials (3014 patients; 2768 controls) were analyzed. Results The overall effect size of SCIT for symptom score (SMD, −0.92; 95%CI, −1.26 to −0.58) was significantly higher than SLIT, both administered via drops (SMD, −0.25; 95% CI, −0.45 to −0.05) and tablets (SMD, −0.40; 95%CI, −0.54 to −0.27). Similar results were reported for medication score (SCIT: SMD, −0.58; 95% CI, −0.86 to −0.30. SLIT drops: SMD, −0.37; 95% CI, −0.74 to −0.00. SLIT tablets SMD, −0.30; 95% CI, −0.44 to −0.16). Conclusions Our results provide indirect but solid evidence that SCIT is more effective than SLIT in controlling symptoms and in reducing the use of antiallergic medications in seasonal allergic rhinoconjuntivitis to grass pollen.
Cyclodextrins can encapsulate various molecules and have exciting applications in supramolecular, pharmaceutical, material, food and environmental chemistry. Typically, the encapsulation into the ...cyclodextrin cavity confers to the guest improved solubility, stability, bioavailability and organoleptic properties. In recent years, cyclodextrin multi-cavity systems have also been studied to encapsulate biomolecules or drugs. This context has inspired us to synthesize and characterize two new β and γ-cyclodextrin dimers and compare their complexation behavior. The two cavities in the same molecule significantly improve the stability of inclusion complexes. Particularly we investigated cholic acid, cholesterol and doxorubicin as guests. The extent of binding between a guest molecule and β and γ-cyclodextrin dimers was established by molecular docking. Cholic acid at physiological pH was chosen as a water-soluble cholesterol analog for the investigation in water by isothermal calorimetry. We found that dimers can include cholate species, cholesterol and doxorubicin better than native cyclodextrins, and the cyclodextrin type tunes the stability of inclusion complexes.
Cyclodextrins can encapsulate various molecules and have exciting applications in supramolecular, pharmaceutical, material, food and environmental chemistry. Typically, the encapsulation into the ...cyclodextrin cavity confers to the guest improved solubility, stability, bioavailability and organoleptic properties. In recent years, cyclodextrin multi-cavity systems have also been studied to encapsulate biomolecules or drugs. This context has inspired us to synthesize and characterize two new β and γ-cyclodextrin dimers and compare their complexation behavior. The two cavities in the same molecule significantly improve the stability of inclusion complexes. Particularly we investigated cholic acid, cholesterol and doxorubicin as guests. The extent of binding between a guest molecule and β and γ-cyclodextrin dimers was established by molecular docking. Cholic acid at physiological pH was chosen as a water-soluble cholesterol analog for the investigation in water by isothermal calorimetry. We found that dimers can include cholate species, cholesterol and doxorubicin better than native cyclodextrins, and the cyclodextrin type tunes the stability of inclusion complexes.
The cyclodextrin dimers can bind the guest involving two possible binding modes.
Purpose
Our study aims at the evaluation of the recently introduced Lima Promade custom-made acetabular device for the treatment of complex acetabular Paprosky 3B defects.
Methods
Between 2016 and ...2018, eight patients with major acetabular osteolysis and multiple revisions history were treated with a custom-made implant in a single centre and by a single surgeon. We assessed patients’ demographics, peri-operative data, and complications and a specific questionnaire was submitted to the surgeon after each procedure.
Results
All the devices were correctly positioned. In two over eight cases, a post-operative dislocation occurred, where extensive soft tissue impairment was present. The questionnaire showed a good pre-operative and intra-operative experience of the surgeon.
Conclusions
The Promade custom-made acetabular system showed encouraging results for complex defects and the entire procedure was positively rated. Further analysis with a higher number of cases and a longer follow-up should be performed for a complete clinical and cost-effective evaluation.
Background
Although the preventive efficacy of allergen immunotherapy (AIT) in the onset of new allergen sensitizations has been asserted by many reviews, position papers, and consensus conferences, ...the evidence available is from only 3 studies. The objective of this work was a systematic review to evaluate the preventive efficacy of AIT in the onset of new allergen sensitizations. The end‐point was the risk difference (RD) in the onset of new allergen sensitizations between patients treated with AIT and pharmacotherapy.
Methods
Computerized bibliographic searches of MEDLINE, EMBASE, and the Cochrane Library (until November 30th, 2016) were done. Random‐effects and fixed‐effects model meta‐analyses were performed. Randomized controlled trials or observational studies comparing children treated with AIT with house dust mite (HDM) to subjects who did not receive AIT, with a long‐term observation period (at least 3 years including treatment and follow‐up) have been included.
Results
Eight studies totaling 721 children (390 treated with AIT and 331 with pharmacotherapy) met the inclusion criteria. The risk of bias was high. Low evidence supports the conclusion that AIT prevents the onset of new allergen sensitizations, with 3 of 8 studies reporting a reduction in the onset of new sensitizations in patients treated with AIT vs pharmacotherapy. Our meta‐analysis found no difference between AIT and pharmacotherapy, with high heterogeneity (RD, −0.10; 95% confidence interval CI, −0.31 to 0.11; p = 0.32; I2 = 91.4%).
Conclusion
The data of this systematic review do not support a preventive effect in the onset of new allergen sensitizations, in children treated with AIT in comparison with those treated with pharmacotherapy.
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