CFTR Cl− channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis

BACKGROUND & AIMS: Cystic fibrosis (CF) is caused by over 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and presents with a widely variable phenotype. Genotype-phenotype studies identified CFTR mutations that were associated with pancreatic sufficiency (PS). Residual Cl- channel function was shown for selected PS mutations in heterologous cells. However, the functional consequences of most CFTR mutations in native epithelia are not well established. METHODS: To elucidate the relationships between epithelial CFTR function, CFTR genotype, and patient phenotype, we measured cyclic adenosine monophosphate (cAMP)-mediated Cl- secretion in rectal biopsy specimens from 45 CF patients who had at least 1 non-DeltaF508 mutation carrying a wide spectrum of CFTR mutations. We compared CFTR genotypes and clinical manifestations of CF patients who expressed residual CFTR-mediated Cl- secretion with patients in whom Cl- secretion was absent. RESULTS: Residual anion secretion was detected in 40% of CF patients, and was associated with later disease onset (P < 0.0001), higher frequency of PS (P < 0.0001), and less severe lung disease (P < 0.05). Clinical outcomes correlated with the magnitude of residual CFTR activity, which was in the range of approximately 12%-54% of controls. CONCLUSIONS: Specific CFTR mutations confer residual CFTR function to rectal epithelia, which is related closely to a mild disease phenotype. Quantification of rectal CFTR-mediated Cl- secretion may be a sensitive test to predict the prognosis of CF disease and identify CF patients who would benefit from therapeutic strategies that would increase residual CFTR activity

Phase I/II study of first-line irinotecan combined with 5-fluorouracil and folinic acid Mayo Clinic schedule in patients with advanced colorectal cancer

BACKGROUND: This multicentre phase I/II study was designed to determine the maximum tolerated dose of irinotecan when combined with 5-fluorouracil and folinic acid according to the Mayo Clinic schedule and to evaluate the activity of this combination as first-line therapy in patients with advanced colorectal cancer. METHODS: Sixty-three patients received irinotecan (250 or 300 mg/m(2), 30- to 90-minute intravenous infusion on day 1), immediately followed by folinic acid (20 mg/m(2)/day) and 5-fluorouracil (425 mg/m(2), 15-minute bolus infusion) days 1 to 5, every four weeks. RESULTS: Diarrhoea was dose limiting at 300 mg/m(2 )irinotecan in combination with 5-fluorouracil and folinic acid, and this was determined to be the maximum tolerated dose. Grade 3–4 neutropenia was the most frequently reported toxicity. The recommended dose of irinotecan for the phase II part of the study was 250 mg/m(2). The response rate for the evaluable patient population was 36% (13/36), and 44% (16 patients) had stable disease (including 19% of minor response). For the intention-to-treat population, the response rate was 29% (14/49) and 35% (17 patients) stable disease (including 14% of minor response). The median time to progression was 7.0 months and the median survival was 12.0 months. Grade 3–4 non-haematological drug-related toxicities included delayed diarrhoea, stomatitis, fatigue, and nausea/vomiting. There were three deaths due to septic shock that were possibly or probably treatment-related. CONCLUSIONS: This regimen of irinotecan in combination with the Mayo Clinic schedule of bolus 5-fluorouracil/folinic acid every four weeks showed activity as first-line therapy in patients with advanced colorectal cancer. In keeping with other published results of studies using bolus 5-fluorouracil combined with irinotecan, the use of this regimen is limited by a relatively high rate of grade 3–4 neutropenia, and the combination of irinotecan and infusional 5-fluorouracil / folinic acid should remain the regimen of first choice

Modulation of Ca2+-activated Cl- secretion by basolateral K+ channels in human normal and cystic fibrosis airway epithelia

Human airway epithelia express Ca-activated Cl channels (CaCC) that are activated by extracellular nucleotides (ATP and UTP). CaCC is preserved and seems to be up-regulated in the airways of cystic fibrosis (CF) patients. In the present study, we examined the role of basolateral K channels in CaCC-mediated Cl secretion in native nasal tissues from normal individuals and CF patients by measuring ion transport in perfused micro Ussing chambers. In the presence of amiloride, UTP-mediated peak secretory responses were increased in CF compared with normal nasal tissues. Activation of the cAMP pathway further increased CaCC-mediated secretion in CF but not in normal nasal mucosa. CaCC-dependent ion transport was inhibited by the chromanol 293B, an inhibitor of cAMP-activated hKvLQT1 K channels, and by clotrimazole, an inhibitor of Ca-activated hSK4 K channels. The K channel opener 1-ethyl-2-benzimidazolinone further increased CaCC-mediated Cl secretion in normal and CF tissues. Expression of hSK4 as well as hCACC-2 and hCACC-3 but not hCACC-1 was demonstrated by reverse transcriptase PCR on native nasal tissues. We conclude that Ca-activated Cl secretion in native human airway epithelia requires activation of Ca-dependent basolateral K channels (hSK4). Co-activation of hKvLQT1 improves CaCC-mediated Cl secretion in native CF airway epithelia, and may have a therapeutic effect in the treatment of CF lung disease

Real-World Use and Effectiveness of Carfilzomib Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma in Europe

This prospective, observational study examined the real-world use of carfilzomib across 11 European countries in adults with relapsed/refractory multiple myeloma (RRMM) who received at least one prior line of therapy. Carfilzomib and dexamethasone (Kd) use, effectiveness and safety were analyzed. In total, 271 patients received Kd among 701 adults enrolled. The median relative dose intensity of carfilzomib was 82.7% (20/56 mg/m2, twice weekly). The overall response rate (ORR) to Kd was 68.8% (95% confidence interval [CI], 62.7&ndash;74.5): 79.2% in second line (2L), 71.6% in third line (3L) and 63.1% in fourth line or later (4L+). The ORR was 59.9% (95% CI, 51.1&ndash;68.1) in the lenalidomide-refractory subgroup and 67.7% (95% CI, 48.6&ndash;83.3) in the not lenalidomide-refractory subgroup. In the anti-CD38 refractory subgroup, the ORR was 51.6% (95% CI, 38.6&ndash;64.5); ORRs were higher when Kd was received at 2L/3L (66.7%) than at 4L+ (49.1%). Overall, patients were treated for a median time of 7.7 months. One-fifth of patients reported treatment-related treatment-emergent adverse events (&ge;grade 3), with a safety profile consistent with previous clinical trials. This study demonstrated the real-world use, effectiveness and safety of Kd in patients with RRMM. Despite the increasing number of new therapeutic strategies to treat RRMM, Kd remains a safe and effective option, even for older, frail and lenalidomide- or anti-CD38 mAb-refractory patients