An exploratory study of body composition as a determinant of epirubicin pharmacokinetics and toxicity

Purpose

Although body composition has emerged as an important predictor of drug efficacy and toxicity, explanations for this association are unclear. Our goal was to investigate relationships between lean body mass (LBM), liver size/function and epirubicin pharmacokinetics (PK) and toxicity.

Methods

Data from a clinical study (n?=?24) of patients with breast cancer receiving adjuvant intravenous FE₁₀₀C chemotherapy were used to examine relationships between LBM, liver size, and epirubicin clearance. Muscle tissue and liver mass were measured by analysis of computerized tomography cross-sectional images, and an extrapolation of muscle mass to total LBM compartment was employed. Population PK analysis of epirubicin was undertaken to test effects of body composition on epirubicin clearance and area under the curve (AUC).

Results

Estimated LBM was extremely variable in this cohort ranging from 32.9 to 67.3?kg. LBM was associated with neutrophil nadir (r?=?0.5, P?=?0.023), and mean LBM was lower for patients presenting with toxicity compared to those where toxicity was absent (41.6 vs. 56.2?kg, P?=?0.002); 33% of variance in clearance was explained by LBM and aspartate aminotransferase (AST). Liver mass was not related to epirubicin clearance likely due to larger livers presenting with larger fat content, but liver attenuation (degree of fat infiltration) and AST were associated with AUC.

Conclusion

To our knowledge, this is the first study to examine relationships between LBM, liver mass/function and epirubicin PK and toxicity. This exploratory work investigates the notion of organs and tissues having distinctive contributions to the distribution and metabolism of antineoplastic drugs.     

颈动脉粥样硬化疾病的处理——美国血管外科学会临床实践指南

美国血管外科学会（SVS）任命了一个专家委员会制定颈动脉狭窄处理的循证临床指南。在制定临床实践推荐意见过程中，该委员会使用系统评价对当前最佳的证据进行了总结，采用GRADE标准对推荐意见的强度（强烈推荐为GRADEI级，一般推荐为GRADEⅡ级）和证据的质量（高、中、低和极低）进行了分级。对于轻度颈动脉狭窄患者（有症状患者狭窄程度〈50％和无症状患者狭窄程度〈60％），推荐进行最佳的内科治疗而非血管重建术（I级推荐，高质量证据）。对于有症状中到重度狭窄患者（狭窄程度〉150％），推荐行颈动脉内膜切除术（CEA）＋最佳的内科治疗（I级推荐，高质量证据）。对于围手术期风险高的有症状中到重度狭窄患者（狭窄程度≥50％），建议采用颈动脉支架置入术作为其替代治疗手段（Ⅱ级推荐，低质量证据）。对于中到重度狭窄的无症状患者（狭窄程度≥60％），只要围手术期风险较低，就推荐行CEA＋内科治疗（I级推荐，高质量证据）。对于中到重度狭窄的无症状患者（狭窄程度≥60％），不推荐行颈动脉支架置入术（I级推荐，低质量证据）。颈动脉狭窄≥80％但存在CEA高危解剖学风险的患者可能是一个例外。     

Occurrence of the t(2;5)(p23;q35) in non-Hodgkin's lymphoma

Primary CD30(Ki-1)-positive anaplastic large-cell lymphoma (ALCL) is considered by some to be a distinct clinicopathologic entity associated with the t(2;5) (p23;q35). However, the specificity of t(2;5) for ALCL has not been carefully studied. Therefore, we performed a detailed analysis of all cases of ALCL with abnormal cytogenetics results in the Nebraska Lymphoma Study Group registry, as well as all other cases of non-Hodgkin's lymphoma with t(2;5) in the registry. We found the t(2;5) in only five of 10 cases of ALCL, four of whom were young patients. However, we also found the t(2;5) in 11 other cases of nonanaplastic lymphoma, including eight children with typical peripheral T-cell lymphomas of various types. The t(2;5) was also found in three older adults with B-cell lymphomas of various types. Thus, the t(2;5) was not specific for CD30+ ALCL. However, t(2;5) may define a clinicopathologic entity in children and young adults characterized by variable morphologies with a T-cell or indeterminate phenotype, CD30-positivity, nodal disease with frequent extranodal involvement, advanced stage, and an excellent response to therapy, including bone marrow transplantation for relapsed disease. The clinical relevance of the t(2;5) in older patients requires further study.     

Adiposity is related to gender differences in impaired stress-induced pressure natriuresis

The purpose of this study was to determine if there are gender differences in stress-induced pressure natriuresis and to examine the effects of adiposity on these differences. The subjects were 151 boys and 141 girls 15 to 18 years of age who underwent a 5-hour stress protocol (2-hour prestress, 1-hour stress, 2-hour poststress) after being brought into similar levels of sodium balance. The gender-by-condition interaction was significant for systolic and diastolic blood pressure (P=0.001 for both), and the effect of condition was significant for sodium excretion (P=0.001). Systolic blood pressure was higher for boys throughout the protocol (P=0.001 for each) and correlated with body mass index at each condition (range in r=0.28 to 0.35; P<0.001 for each). Hemodynamically, in boys body mass index was correlated with cardiac output during stress (r=0.23; P=0.006), which was correlated with systolic blood pressure (r=0.21; P=0.01). With respect to natriuresis, body mass index was inversely correlated with sodium excretion during stress (r=-0.22; P=0.008) and positively correlated with angiotensin II in a subsample of boys (n=89: r=0.31; P=0.003). The inverse correlation between angiotensin II and sodium excretion during stress approached significance (r=-0.17; P<0.06). Similar results were not observed for girls. In conclusion, gender differences in stress-induced pressure natriuresis appear to be related to the influence of adiposity on both blood pressure and natriuresis.     

Trastuzumab-induced cardiotoxicity in elderly women with HER-2-positive breast cancer: a meta-analysis of real-world data

Background: We conducted a meta-analysis to assess the overall risk of cardiac toxicity associated with trastuzumab treatment in elderly breast cancer patients.

Methods: We searched databases from PubMed, EMBASE and Cochrane Central Registry of Controlled Trials to identify relevant studies. Statistical analyses were conducted to calculate the incidence rate, overall hazard ratio (HR) and 95% CIs using a fixed effects model.

Results: A total of 116,342 and 360 elderly patients from five cohort studies and two randomized clinical trials (RCTs) were included for analysis. The pooled incidences of symptomatic congestive heart failure (CHF) and CHF/HF/CM were 6.4% (95% CI 4.1% – 9.4) and 16.4% (95% CI 16.19% – 16.61) in patients with median age of 67.5 years from two RCTs and in patients with median age of 67.5 (60 – 75), 71 (66 – 80+), 74.5 (65 – 89), 75 (66 – 81+) and 79.5 (60 – 99) from five cohort studies, respectively. Trastuzumab was significantly correlated with an increased risk of defined cardiac toxicities in five cohort studies (HR = 1.89, 95% CI 1.72 – 2.07, p < 0.00001) and two RCTs (HR = 3.00, 95% CI 1.71, 5.26, p < 0.00001). Sub-group analysis showed that the anthracycline-based chemotherapy increased the risk of CHF/HF and CM in patients among five cohort studies (HR = 2.16, 95% CI: 1.8 – 1.87, p < 0.00001).

Conclusion: Trastuzumab is likely associated with an increased risk of cardiac toxicity in elderly patients with HER-2-positive breast cancer. Carefully monitoring cardiac function in elderly patients receiving trastuzumab, particularly with concurrent use of anthracycline, is warranted.     

l‐Methionine anti‐biofilm activity against Pseudomonas aeruginosa is enhanced by the cystic fibrosis transmembrane conductance regulator potentiator,ivacaftor

Background

Biofilms may contribute to refractory chronic rhinosinusitis (CRS), as they lead to antibiotic resistance and failure of effective clinical treatment. l ‐Methionine is an amino acid with reported biofilm‐inhibiting properties. Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator with mild antimicrobial activity via inhibition of bacterial DNA gyrase and topoisomerase IV. The objective of this study was to evaluate whether co‐treatment with ivacaftor and l ‐methionine can reduce the formation of Pseudomonas aeruginosa biofilms.

Methods

P aeruginosa (PAO‐1 strain) biofilms were studied in the presence of l ‐methionine and/or ivacaftor. For static biofilm assays, PAO‐1 was cultured in a 48‐well plate for 72 hours with stepwise combinations of these agents. Relative biofilm inhibitions were measured according to optical density of crystal violet stain at 590 nm. Live/dead assays (BacTiter‐Glo? assay, Promega) were imaged with laser scanning confocal microscopy. An agar diffusion test was used to confirm antibacterial effects of the drugs.

Results

l ‐Methionine (0.5 μM) significantly reduced PAO‐1 biofilm mass (32.4 ± 18.0%; n = 4; p < 0.001) compared with controls. Low doses of ivacaftor alone (4, 8, and 12 μg/mL) had no effect on biofilm formation. When combined with ivacaftor (4 μg/mL), a synergistic anti‐biofilm effect was noted at 0.05 μM and 0.5 μM of l ‐methionine (two‐way analysis of variane, p = 0.0415) compared with corresponding concentrations of l ‐methionine alone.

Conclusion

Ivacaftor enhanced the anti‐biofilm activity of l ‐methionine against the PAO‐1 strain of P aeruginosa. Further studies evaluating the efficacy of ivacaftor/l ‐methionine combinations for P aeruginosa sinusitis are planned.

     

Bezoar: an Unusual Palpable Mass in the Right Iliac Fossa

A 64-year-old gentleman presented with a 12-h history of right iliac fossa pain. On examination, the patient had a tender 8 × 6 cm mass in the right iliac fossa with localised peritonitis. The working diagnosis at this time was an appendix mass or caecal cancer. A computed tomography scan revealed the characteristic ‘bird''s nest’ appearance of a bezoar. On further questioning, the patient confessed to regularly ‘binging’ on grapes. The patient described passing the mass and his symptoms completely resolved. This appears to be the only documented case of a bezoar affecting the ascending colon.