Highlights • BTK is a TEC-family kinases member, expressed in lymphocytes and other cell subtypes. • TEC kinases inhibition by Ibrutinib has promising results in cancer cellular models. • Ibrutinib ...is able to modify the tumor microenvironment with therapeutic implications. • BTK inhibitors may have synergistic effect with other active drugs in solid tumors.
After primary radiotherapy, biochemical recurrence is defined according to the Phoenix criteria as a prostate-specific antigen (PSA) value >2 ng/ml relative to the nadir. Several studies have shown ...that prostate-specific membrane antigen (PSMA)-ligand positron emission tomography/computed tomography (PET/CT) can help in detecting recurrence in patients with low PSA values. This study aimed to assess the detection rate and patterns of PSMA-ligand PET/CT uptake in patients with suspected biochemical recurrence after primary radiotherapy and with PSA levels below the Phoenix threshold.
The meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Articles providing data on patients with suspected prostate cancer recurrence after primary radiotherapy with a PSA value below the Phoenix threshold and who underwent PSMA-ligand PET/CT were included. Quality assessment was carried out using the Quality Assessment of Diagnostic Accuracy Studies-2 tool (QUADAS-2).
In total, five studies were included, recruiting 909 patients (202 with PSA ≤2 ng/ml). The PSMA-ligand detection rate in the patients with ≤2 ng/ml ranged from 66 to 83%. The most frequent source of PSMA-ligand PET/CT uptake was local recurrence, followed by lymph node metastasis and bone metastasis. PSMA-ligand PET/CT uptake due to local-only recurrence was more likely in patients with PSA ≤2 ng/ml compared with PSA > 2 ng/ml: risk ratio 0.72 (95% confidence interval 0.58-0.89), P = 0.003. No significant differences were observed in the detection of PSMA-ligand uptake in other areas. Limitations include a lack of biopsy confirmation, cohort reports with small sample sizes and a potentially high risk of bias.
A significant detection of PSMA-ligand-avid disease was observed in patients with PSA levels below the Phoenix threshold. There was a higher likelihood of detecting local-only uptake when the PSA value was ≤2 ng/ml. The findings suggest that a critical review of the Phoenix criteria may be warranted in the era of PSMA-ligand PET/CT and highlight the need for further prospective trials.
Background
The studies IMvigor 210 cohort 2 and IMvigor211 evaluated the efficacy of atezolizumab in patients with locally advanced or metastatic urothelial cancer (mUC) upon progression to ...platinum-based chemotherapy worldwide. Yet, the real impact of this drug in specific geographical regions is unknown.
Materials and methods
We combined individual-level data from the 131 patients recruited in Spain from IMvigor210 cohort 2 and IMvigor211 in a pooled analysis. Efficacy and safety outcomes were assessed in the overall study population and according to PD-L1 expression on tumour-infiltrating immune cells.
Results
Full data were available for 127 patients; 74 (58%) received atezolizumab and 53 (42%) chemotherapy. Atezolizumab patients had a numerically superior median overall survival although not reaching statistical significance (9.2 months vs 7.7 months). No statistically significant differences between arms were observed in overall response rates (20.3% vs 37.0%) or progression-free survival (2.1 months vs 5.3 months). Nonetheless, median duration of response was superior for the immunotherapy arm (non-reached vs 6.4 months;
p
= 0.005). Additionally, among the responders, the 12-month survival rates seemed to favour atezolizumab (66.7% vs 19.9%). When efficacy was analyzed based on PD-L1 expression status, no significant differences were found. Treatment-related adverse events of any grade occurred more frequently in the chemotherapy arm 46/57 (81%) vs 44/74 (59%).
Conclusion
Patients who achieved an objective response on atezolizumab presented a longer median duration of response and numerically superior 12 month survival rates when compared with chemotherapy responders along with a more favorable safety profile. PD-L1 expression did not discriminate patients who might benefit from atezolizumab.
Neuroendocrine neoplasms (NENs) are considered a heterogeneous and rare entity. Its natural history is influenced by multiple clinicopathological characteristics, which guide the management of these ...patients. The development of molecular biology reveals that the PI3K–AKT–mTOR pathway plays a relevant role in tumorigenesis and progression of NENs. Mammalian target of rapamycin (mTOR) inhibitors, targeted agents that block this pathway, has improved outcomes in neuroendocrine tumors (NETs). Different therapeutic approaches, such as somatostatin analogs, chemotherapy, peptide receptor radionuclide therapy, and targeted agents, have shown benefits in the treatment of NETs. However, there are not any established prognostic or predictive biomarkers to select the best therapy option to individualize treatment. Although a relation between alterations in the PI3K–AKT–mTOR pathway and clinical outcomes has not been found, these anomalies are considered attractive biomarkers. Additional molecular analysis should be integrated in future clinical trials’ design to identify potential predictive or prognostic biomarkers.
Summary
Background
It is difficult to find a causal relationship between exposure to Alternaria spores and the development of asthma symptoms in sensitized individuals due to the complexity of ...clinical situations in which positive diagnostic tests are often found.
Objective
To analyse the diagnostic efficiency of skin testing (ST) and serum‐specific IgE to Alternaria, based on the results of a bronchial specific challenge with Alternaria extracts.
Methods
Seventy‐four asthmatic patients sensitized to Alternaria underwent a specific bronchial challenge with this mould. Skin‐testing weal sizes, serum‐specific IgE values (CAP‐system) and bronchial challenge results were analysed by receiver operating characteristics curves (ROC curves) and logistic regression. The sensitivity, specificity, positive and negative predictive values were calculated for different cut‐off points.
Results
Bronchial challenges to Alternaria elicited a positive result in 45 patients (61%). Skin prick testing almost perfectly predicted the outcome of bronchoprovocation tests (area under the ROC curve of 0.957), whereas intradermal skin testing had moderate efficacy. A negative result for skin prick test (SPT) showed a 4% probability of a positive bronchial challenge in the logistic regression analysis. However, weals around 5.5 mm in diameter had 90% probability of a positive challenge. Quantification of serum‐specific IgE correctly classified 86% of the cases. In the logistic regression analysis, a CAP value 16 kUA/L predicted a positive bronchial challenge result with 99% accuracy, whereas for a CAP value <0.35 kUA/L, this probability was 33%.
Conclusions and Clinical Relevance
Most asthmatic patients with positive SPT results to Alternaria would have a positive bronchial challenge. As atmospheric mould levels may vary significantly with the weather conditions, sensitized patients should be instructed on the risk situations, environmental control measures and the importance of correct medication compliance. Immunotherapy with Alternaria could also be taken into account as a valid therapeutic option.
Cite this as: C. Fernández, E. Bevilacqua, N. Fernández, P. Gajate, A. G. de la Cámara, M. Garcimartín, R. Vives and J. Rodríguez, Clinical & Experimental Allergy, 2011 (41) 649–656.
The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear.
In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned ...patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point.
A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval CI, 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group.
In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).
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