Emerging treatment using tubulin inhibitors in advanced non-small cell lung cancer

Introduction: Tubulin inhibitors including taxanes and vinca alkaloids are important components of chemotherapy regimens used in advanced non-small cell lung cancer (NSCLC). Despite a treatment paradigm shift due to molecularly-targeted therapies and immunotherapy, a majority of patients will receive chemotherapy during their treatment course. Either used alone or in combination, tubulin inhibitors have demonstrated clinical benefits in different settings of lung cancer management.

Areas covered: This review first discusses FDA-approved tubulin inhibitors for NSCLC, such as paclitaxel, docetaxel, vinorelbine, and nab-paclitaxel. The article then provides a summary of novel tubulin inhibitors, including cabazitaxel, eribulin, ixabepilone, patupilone, plinabulin, new colchicine analogues and others. It also discusses new tubulin inhibitor combinations with immunotherapy (PD-1/PD-L1 inhibitors) and molecularly-targeted therapies (e.g. anti-angiogenic agents, mTOR inhibitors, heat shock protein 90 inhibitors, MEK inhibitors, and anti-HER3 agents). Lastly, emerging data on potential resistance mechanisms and predictive biomarkers for tubulin inhibitors are explored.

Expert opinion: Tubulin inhibitors will likely continue to play important roles in NSCLC management due to the advent of novel agents and combinations. Through further understanding of tumor biology, investigation of drug resistance, and development of predictive biomarkers, we will be better positioned to incorporate microtubule inhibition into patient specific treatment strategies.     

Analysis of vancomycin use and associated risk factors in a university teaching hospital: a prospective cohort study

Background  

Vancomycin use is considered inappropriate in most hospitals. A particular concern is the recent emergence of S. aureus with decreased susceptibility to vancomycin, making it important to reduce overall exposure to vancomycin to minimize the incidence of VRE (vancomycin-resistant enterococci). The aim of this work was to analyze the use of vancomycin and the risk factors associated with inappropriate treatment.     

Characterization of novel Mycobacterium tuberculosis pncA gene mutations in clinical isolates from the Ukraine

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis cases in the Ukraine are increasing. Pyrazinamide (PZA) is critically important for first- and second-line tuberculosis (TB) treatment regimes. However, PZA drug susceptibility testing is time consuming and technically challenging. The present study utilized Next-generation sequencing (NGS) to identify mutations in the pncA gene from clinical isolates and to assess the prevalence of pncA gene mutations in MDR/XDR-TB patients. Clinical isolates were inactivated in molecular transport media and shipped from Kharkiv, Ukraine, to San Antonio, TX. Whole-genome and targeted pncA gene sequencing was carried out using Illumina MiSeq instrumentation. Mutations were noted in 67 of 91 (74%) clinical isolates comprising substitutions, insertions, and deletions in the pncA coding and upstream promoter region. Of 45 mutation types, there were 11 novel, i.e., to date unknown, pncA mutations identified of which 3 were confirmed PZA resistant. Seven isolates contained mixed base mutations, whereas 4 harbored doubled mutations. Data reported here further support use of NGS for pncA gene characterization and may contribute in significant fashion to PZA therapy, especially in MDR- and XDR-TB patients.     

Fetal growth from mid‐ to late pregnancy is associated with infant development: the Generation R Study

Aim The aim of this study was to investigate within a population‐based cohort of 4384 infants (2182 males, 2202 females) whether fetal growth from early pregnancy onwards is related to infant development and whether this potential relationship is independent of postnatal growth. Method Ultrasound measurements were performed in early, mid‐, and late pregnancy. Estimated fetal weight was calculated using head and abdominal circumference and femur length. Infant development was measured with the Minnesota Infant Development Inventory at 12 months (SD 1.1mo, range 10–17mo). Information on postnatal head size and body weight at 7 months was obtained from medical records. Results After adjusting for potential confounders and for postnatal growth, faster fetal weight gain from mid‐ to late pregnancy predicted a reduced risk of delayed social development (odds ratio [OR] 0.82; 95% confidence interval [CI] 0.71–0.95, p=0.008), self‐help abilities (OR 0.84; 95% CI 0.73–0.98, p=0.023), and overall infant development (OR 0.65; 95% CI 0.49–0.87, p=0.003). Similar findings were observed for fetal head growth from mid‐ to late pregnancy. Interpretation Faster fetal growth predicts a lower risk of delayed infant development independent of postnatal growth. These results suggest that reduced fetal growth between mid‐ and late pregnancy may determine subsequent developmental outcomes.     

A case of intestinal MALToma with co-existent tuberculosis and Peutz-Jeghers polyp

A 22-year-old male patient underwent a segmental resection of the ileum due to clinical symptoms of bowel obstruction and radiological evidence of ileal wall thickening and enlarged mesenteric nodes. Histopathological examination of the resected specimen revealed an extranodal marginal zone B-cell lymphoma(MALToma) of the intestine and tuberculous lesions along with a solitary Peutz-Jeghers polyp. The case is presented for its rarity and to stress upon the clinical and radiological challenges that arise when lymphomas and tuberculous lesions co-exist at the same site.KEY WORDS: Intestinal lymphoma, MALToma, marginal zone lymphoma, Peutz-Jeghers polyp, tuberculosis     

Plateletpheresis in the management of thrombocytosis

Acute thrombotic and hemorrhagic manifestations of thrombocytosis associated with myeloproliferative disorders may be life threatening. Conventional therapy with radioisotopes and/or cytotoxic drugs may require weeks for effective control of platelet counts. In five patients, plateletpheresis by discontinuous-flow (Haemonetics) or continuous-flow (Aminco Celltrifuge) centrifugation was used as a means of reducing platelet counts acutely. With each procedure, approximately 2-9 X 10(12) platelets were removed, resulting in decrements in platelet counts and relief of symptoms. Plateletpheresis is a useful and safe acute means of controlling platelet counts in myeloproliferative disorders.     

Dramatic elevations of interleukin-6 and acute-phase reactants in athletes participating in the ultradistance foot race spartathlon: severe systemic inflammation and lipid and lipoprotein changes in protracted exercise

CONTEXT AND OBJECTIVE: Plasma IL-6, the serum inflammatory markers C-reactive protein (CRP) and serum amyloid A (SAA), and the tissue destruction marker-free plasma DNA, as well as the circulating lipid profile, were examined in athletes participating in the ultradistance foot race of the 246-km Spartathlon. SETTING, DESIGN, AND PARTICIPANTS: This race consists of continuous, prolonged, brisk exercise. Blood samples were obtained from 15 male athletes, who finished the race in less than 36 h, taken before, at the end of, and 48 h after the end of the race. RESULTS: IL-6, CRP, SAA, and free plasma DNA levels markedly increased (by 8000-, 152- 108-, and 10-fold, respectively) over the baseline at the end of the race. However, IL-6 levels returned to normal by 48 h, whereas CRP, SAA, and free plasma DNA remained elevated. The mean values of cholesterol, triglycerides, low-density lipoprotein, and apolipoprotein B decreased to a minimum value at the end of the race and remained low 48 h after the race. High-density lipoprotein levels, on the other hand, were mildly increased at the end of the race (P < 0.015) and decreased to normal 48 h after the race. Apolipoprotein AI levels decreased significantly during the time course of the exercise and remained low 48 h after the race (P < 0.001). CONCLUSIONS: These observations suggest that continuous, prolonged, moderate-intensity exercise is associated with markedly elevated IL-6 and acute-phase reactant concentrations, peripheral tissue damage, and significant changes in serum lipid levels. The biochemical changes observed during the Spartathlon amount to a potent systemic inflammatory response, which might explain severe cardiovascular events that occur during prolonged exercise in compromised individuals.     

Cystatin C levels in patients with β-thalassemia during deferasirox treatment

Deferasirox (Exjade®) is a once-daily, oral iron chelator approved for the treatment of transfusional iron overload. This study was conducted to analyze changes in cystatin C concentration, an endogenous marker of glomerular filtration rate (GFR), in patients with thalassemia receiving daily deferasirox therapy over a period of at least 9 months. One hundred and fifty β-thalassemia patients were treated with deferasirox at doses of 20–40 mg/kg/day for 9 consecutive months. Cystatin C concentrations were measured at regular intervals and GFR was calculated according to the cystatin C-based prediction equation. Plasma concentrations of NGAL protein and NT-proBNP were also monitored as indicators of renal function and LVEF, respectively. Serum ferritin concentration was also measured to assess iron overload. Throughout the 9 months of deferasirox treatment cystatin C concentration remained stable (p > 0.850). The baseline cystatin C mean values were 0.97 ± 0.27 mg/L and reached a maximum of 1.01 ± 0.29 mg/L at 4 months of treatment. No correlation was found between cystatin C and NGAL concentrations (p > 0.674). Cystatin C and NT-proBNP concentrations correlated positively with a binomial equation (p < 0.004), as also did cystatin C and serum ferritin (p < 0.001). These findings suggest that slight changes of cystatin C during deferasirox treatment may not reflect renal injury. However hemodynamic signals such as LVEF alterations and iron mobilization do appear to affect changes in cystatin C concentration.