Reprogramming the tumor microenvironment to improve the efficacy of cancer immunotherapies.

The immunotherapeutic approaches based on checkpoint inhibitors, tumor vaccination, immune cell-based therapy, and cytokines were developed to engage the patient's immune system against cancer and better survival of them. While potent, however, preclinical and clinical data have identified that abnormalities in the tumor microenvironment (TME) can affect the efficacy of immunotherapies in some cancers. It is therefore imperative to develop new therapeutic interventions that will enable to overcome tumor-supportive TME and restrain anti-tumor immunity in patients that acquire resistance to current immunotherapies. Therefore, recognition of the essential nature of the tolerogenic TME may lead to a shift from the immune-suppressive TME to an immune-stimulating phenotype. Here, we review the composition of the TME and its effect on tumor immunoediting and then present how targeted monotherapy or combination therapies can be employed for reprogramming educated TME to improve current immunotherapies outcomes or elucidate potential therapeutic targets.

The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis.

Outcome measures to assess therapeutic interventions in cystic fibrosis (CF) patients with mild lung disease are lacking. Our aim was to determine if the lung clearance index (LCI) can detect a treatment response to dornase alfa in paediatric CF patients with normal spirometry. CF patients between 6-18 yrs of age with FEV(1 )≥ 80% pred were eligible. In a crossover design, 17 patients received 4 weeks of dornase alfa and placebo in a randomised sequence separated by a 4-week washout period. The primary end-point was the change in LCI from dornase alfa versus placebo. A mixed model approach incorporating period-dependent baselines was used. The mean ± sd age was 10.32 ± 3.35 yrs. Dornase alfa improved LCI versus placebo (0.90 ± 1.44; p = 0.022). Forced expiratory flow at 25-75% expired volume measured by % pred and z-scores also improved in subjects on dornase alfa (6.1% ± 10.34%; p = 0.03 and 0.28 ± 0.46 z-score; p = 0.03). Dornase alfa significantly improved LCI. Therefore the LCI may be a suitable tool to assess early intervention strategies in this patient population.

Non-Hodgkin's lymphoma in Saudi Arabia: prognostic factors and an analysis of the outcome of combination chemotherapy only, for both localized and advanced disease.

Seventy-eight previously untreated patients with clinical stage (CS) I and II (42 patients) and CS III and IV (36 patients) and non-Hodgkin's lymphoma (NHL) were treated with systemic chemotherapy only. All patients had intermediate or high grade lymphoma. Two different regimens were used: bleomycin, adriamycin, cyclophosphamide, vincristine and prednisone (BACOP); and a combination of methotrexate with folinic acid rescue, epirubicin, cyclophosphamide, vincristine, prednisone and bleomycin (MECOP-B), for 57 and 21 patients respectively. Objective clinical remission was achieved in 90% of the cases, of which 73% were complete. Complete remission (CR) was demonstrated in 90% and 53% of patients with CS I + II and III + IV respectively (P = 0.0008). Two variables, bone marrow and liver involvement, were negatively associated with CR rate in a multivariate analysis. The actuarial overall survival for the entire group was 65%. The median survival for complete responders has not been reached, but a projected 80% relapse-free survival at 3 years is estimated. The Cox proportional hazards model predicted that advanced stage (CS III and IV) and pretreatment lactic dehydrogenase serum level above 400 iu/l (N less than 200 iu/l) independently influenced survival adversely. The latter prognostic variables were used to identify several groups with different risk probabilities. Despite an apparent comparability between patients receiving the two regimens, no significant difference in response or survival rates was noted between the two protocols. We conclude that the results of systemic chemotherapy compared favorably with radiation therapy for early stage disease and is an acceptable strategy for developing countries with limited availability of radiotherapy facilities. Based on certain risk factors, therapy should be individualized so that more intense regimens, with or without radiation, should be offered only to those patients in the high risk group at highly specialized centers.