SARS-Cov2 infection may trigger lung inflammation and acute-respiratory-distress-syndrome (ARDS) that requires active ventilation and may have fatal outcome. Considering the severity of the disease ...and the lack of active treatments, 14 patients with Covid-19 and severe lung inflammation received inhaled adenosine in the attempt to therapeutically compensate for the oxygen-related loss of the endogenous adenosine→A2A adenosine receptor (A2AR)-mediated mitigation of the lung-destructing inflammatory damage. This off label-treatment was based on preclinical studies in mice with LPS-induced ARDS, where inhaled adenosine/A2AR agonists protected oxygenated lungs from the deadly inflammatory damage. The treatment was allowed, considering that adenosine has several clinical applications.
Fourteen consecutively enrolled patients with Covid19-related interstitial pneumonitis and PaO2/FiO2 ratio<300 received off-label-treatment with 9 mg inhaled adenosine every 12 hours in the first 24 hours and subsequently, every 24 days for the next 4 days. Fifty-two patients with analogue features and hospitalized between February and April 2020, who did not receive adenosine, were considered as a historical control group. Patients monitoring also included hemodynamic/hematochemical studies, CTscans, and SARS-CoV2-tests.
The treatment was well tolerated with no hemodynamic change and one case of moderate bronchospasm. A significant increase (> 30%) in the PaO2/FiO2-ratio was reported in 13 out of 14 patients treated with adenosine compared with that observed in 7 out of52 patients in the control within 15 days. Additionally, we recorded a mean PaO2/FiO2-ratio increase (215 ± 45 vs. 464 ± 136, P = 0.0002) in patients receiving adenosine and no change in the control group (210±75 vs. 250±85 at 120 hours, P>0.05). A radiological response was demonstrated in 7 patients who received adenosine, while SARS-CoV-2 RNA load rapidly decreased in 13 cases within 7 days while no changes were recorded in the control group within 15 days. There was one Covid-19 related death in the experimental group and 11in the control group.
Our short-term analysis suggests the overall safety and beneficial therapeutic effect of inhaled adenosine in patients with Covid-19-inflammatory lung disease suggesting further investigation in controlled clinical trials.
Lack of specific antiviral treatment for COVID-19 has resulted in long hospitalizations and high mortality rate. By harnessing the regulatory effects of adenosine on inflammatory mediators, we have ...instituted a new therapeutic treatment with inhaled adenosine in COVID-19 patients, with the aim of reducing inflammation, the onset of cytokine storm, and therefore to improve prognosis. The use of inhaled adenosine in COVID19 patients has allowed reduction of length of stay, on average 6 days. This result is strengthened by the decrease in SARS-CoV-2 positive days. In treated patients compared to control, a clear improvement in PaO
/FiO
was observed together with a reduction in inflammation parameters, such as the decrease of CRP level. Furthermore, the efficacy of inhaled exogenous adenosine led to an improvement of the prognosis indices, NLR and PLR. The treatment seems to be safe and modulates the immune system, allowing an effective response against the viral infection progression, reducing length of stay and inflammation parameters.
Pembrolizumab (mAb to PD-1) has been recently approved for the therapy of pretreated urothelial cancer. Despite the efficacy, it is often accompanied by unpredictable and sometime severe ...immune-related (ir) adverse events (AEs). Here, we report the clinical and immune–biological characterization of a patient with a metastatic bladder cancer who developed myositis signs (M) and a myasthenia-like syndrome (MLS) during treatment with pembrolizumab. The patient presented an autoimmunity-associated HLA haplotype (HLA-A*02/HLA-B*08/HLA-C*07/HLA-DRB1*03) and experienced an increase in activated CD8 T-cells along the treatment. The symptomatology regressed after pembrolizumab discontinuation and a pyridostigmine and steroids-based therapy. This is the first report of concurrent M and MLS appearance in cancer patients receiving pembrolizumab. More efforts are needed to define early the risk and the clinical meaning of irAEs in this setting.
Tumor-infiltrating T cell rescue by programmed cell death receptor-1 (PD-1)/PD-1 ligand-1 (PD-L1) immune checkpoint blockade is a recommended treatment for malignant diseases, including metastatic ...non-small-cell lung cancer (mNSCLC), malignant melanoma (MM), head and neck, kidney, and urothelial cancer. Monoclonal antibodies (mAbs) against either PD-1 or PD-L1 are active agents for these patients; however, their use may be complicated by unpredictable immune-related adverse events (irAEs), including immune-related pneumonitis (IRP). We carried out a retrospective multi-institutional statistical analysis to investigate clinical and biological parameters correlated with IRP rate on a cohort of 256 patients who received real-world treatment with PD-1/PD-L1 blocking mAbs. An independent radiological review board detected IRP in 29 patients. We did not find statistical IRP rate correlation with gender, tumor type, specific PD-1 or PD-L1 blocking mAbs, radiation therapy, inflammatory profile, or different irAEs. A higher IRP risk was detected only in mNSCLC patients who received metronomic chemotherapy +/- bevacizumab compared with other treatments prior PD-1/PD-L1 blockade. Moreover, we detected a strong correlation among the IRP rate and germinal expression of HLA-B*35 and DRB1*11, alleles associated to autoimmune diseases. Our findings may have relevant implications in predicting the IRP rate in mNSCLC patients receiving PD-1/PD-L1 blockade and need to be validated on a larger patient series.
Carboplatin is the cornerstone of ovarian cancer (OC) treatment, while platinum-response, dependent on interindividual variability, is the major prognostic factor for long-term outcomes. This ...retrospective study was focused on explorative search of genetic polymorphisms in the Absorption, Distribution, Metabolism, Excretion (ADME) genes for the identification of biomarkers prognostic/predictive of platinum-response in OC patients. Ninety-two advanced OC patients treated with carboplatin-based therapy were enrolled at our institution. Of these, we showed that 72% of patients were platinum-sensitive, with a significant benefit in terms of OS (
= 0.001). We identified an inflammatory-score with a longer OS in patients with lower scores as compared to patients with the maximum score (
= 0.001). Thirty-two patients were genotyped for 1931 single nucleotide polymorphisms (SNPs) and five copy number variations (CNVs) by the DMET Plus array platform. Among prognostic polymorphisms, we found a potential role of UGT2A1 both as a predictor of platinum-response (
= 0.01) and as prognostic of survival (
= 0.05). Finally, we identified 24 SNPs related to OS. UGT2A1 correlates to an "inflammatory-score" and retains a potential prognostic role in advanced OC. These data provide a proof of concept that warrants further validation in follow-up studies for the definition of novel biomarkers in this aggressive disease.
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Dec 2018, 7 consecutive patients, ( CLL n = 1; FL n = 3; DLBCL n= 1 AEA n=1,ITP n=1), were enrolled in the study. Median age of the patients was 68 years (range, 28-87). The pharmacoeconomic ...analysis included assessment of direct costs ( hospital inpatient, physician inpatient, physician outpatient, emergency department nursing home care, specialists' and other health professionals' care, diagnostic tests, prescription drugs and drug sundries, and medical supplies),indirect costs incurred by care recipients and unpaid caregivers, including time, productivity and travel cost.
Results Rituximab subcutaneous formulation was administered at a fixed dose of 1400 mg with a frequency related to the type and the phase of the treated disease. Before starting MabThera subcutaneous injections, all patients received beforehand, a full dose of Rituximab by intravenous infusion. Premedication with an anti-pyretic an antihistaminic and prednisone , was given orally in the evening before and the morning of the subcutaneous administration the infusion was carried out by the staff of the home care unit together with a doctor. All the procedure was controlled by the hospital specialist through a smart-phone. Median age of the patients was 58 years (range, 32-83). Median number of courses delivered to each patient was 6 (range, 4- 12) .Adherence to treatment was 100%.No Infusion related adverse reactions have been observed.
Conclusion
In our experience, despite the high percentage of elderly patients of whom 36% living in rural area, it was possible to give treatment to all patients with high adherence and satisfaction. There has been a reduction in direct medical costs due to less use of hospitalization, a reduction of indirect costs by 70% due to the lower number of working days lost and a drastic reduction of travel costs, with the same safety of administration.
No relevant conflicts of interest to declare.
Background and aim
Tetracosactide Acetate (SR-TA) stimulates the release of corticosteroids such as cortisol from the adrenal gland. It is absorbed on to a zinc phosphate complex which ensures the ...sustained release of the active substance from the intramuscular injection site. SR-TA is currently used in the management of ulcerative colitis and Crohn's disease, juvenile/adult rheumatoid arthritis and osteoarthrosis. However, its properties indicate that this compound may be particularly useful in patients unable to tolerate oral glucocorticoid therapy or where normal therapeutic doses of glucocorticoids turned to be ineffective. Eltrombopag is an oral, non-peptide thrombopoietin receptor agonist that has been shown efficacy and safety in chronic immune thrombocytopenia (ITP) patients not responding to previous therapy. Based on these premises, we treated with a combination of Eltrombopag and SR-TA selected ITP patients undergoing a platelet count fluctuation despite a standard eltrombopag dose was given .
Material and methods
A total of 6 adult patients, female (60%),median (range) age 37 (28 - 54) years, median (range) baseline platelet count 31 (28 - 46) × 109/L, median of 3 (2 - 4) prior ITP therapies, received a combo of Eltrombopag 50 mg by mouth daily and SR-TA 1 mg intramuscularly daily until the target platelet count of 50× 109/L was reached, then a dose of 1mg of SR-TA was given every 3 days; in responding patients , i.e. without platelet count fluctuation, the dose was further reduced to 1mg per week.
Results
5 out of six patients responded to treatment reaching and maintaining the platelet count between 50× 109/L and 100× 109/L. After a median follow-up of 6 months with combo treatment, all patients maintained their response. Self-administration was started by 100% of patients (6/6). No adverse events have been observed.
Our experience has shown that eltrompopag/SR-TA combo is effective and safe in maintaining the platelet count above 50x109/L in those patients not reaching this target with the TPO mimetic alone.
No relevant conflicts of interest to declare.
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Carboplatin is the milestone of epithelial ovarian cancer (EOC) treatment, thus response to platinum is the major prognostic factor. Among platinum-sensitive patients, 40% carry a ...germline or somatic BRCA1/2 mutation. In this scenario a new class of drugs, the PARP inhibitors (PARPis), produced a significant improvement in long-term disease control. In order to make an aggregate evaluation of the impact of these agents, we performed a systematic review and meta-analysis.
Clinical trials were selected by searching “Pubmed” database and abstracts from major cancer meetings. We considered the January 2008 - April 2018 time frame. Progression free survival (PFS) was the primary end-point, toxicities were secondary end-points. Hazard ratios (HRs) of PFS, with confidence intervals, and risk ratios of grade 3–4 toxicity rates, were extracted from retrieved studies and included in the current analysis. Meta-analysis was carried out by the fixed and random effect models. We conducted this meta-analysis to also compare indirectly the efficacy of different PARPis in EOC patients.
Five randomized trials for a total of 1839 patients were selected and included in the final analysis. In particular, we evaluated a BRCA-mutant cohort (871 patients) with a pooled HR 0.25 (95%CI 0.21-0.31) and the BRCA-wild type cohort (836 patients) with a pooled HR 0.41 (95%CI 0.31-0.55), respectively. Regarding safety profile, no significant differences were detected in all grade toxicities, however, taking into account 3–4 grade toxicities and SAEs (severe adverse events), we show that rucaparib-treated patients reported major abdominal pain events, while niraparib-treated patients were associated with the highest percentage of haematological toxicities, hypothesizing a drug effect for the safety analysis. In the indirect comparisons, significant differences were not detected on PFS for the different agents.
We confirm a significant benefit in survival outcome of PARPis for EOC patients with a “class effect” on the bases of narrow CI and indirect comparisons in the different groups. Therefore, we underline that this strategy is of special value in BRCA-mutated patients because genetic testing allows best patient selection for all PARPis with the added value of individualized prevention in familiars.
Taxane‐related peripheral neuropathy (TrPN) is a dose‐limiting toxicity with important interindividual variability. Genetic polymorphisms in absorption, distribution, metabolism, and excretion (ADME) ...genes may account for variability in drug efficacy and/or toxicity. By the use of Affymetrix drug‐metabolizing enzyme and transporter microarray platform, in a retrospective case‐control study, the correlation between ADME polymorphic variants and grades ≥ 2−3‐TrPN was investigated. In a breast cancer (BC) training set, five single‐nucleotide polymorphisms in NR1I3 and UDP‐glucuronosyltransferase (UGT)2B7 genes were correlated to grades ≥ 2−3‐TrPN protection. By receiver operating characteristic curves, the grades ≥ 2−3‐TrPN‐related candidate biomarkers in an independent series of 54 patients with BC (17 cases and 37 controls) were validated. NR1I3 was correlated to paclitaxel‐TrPN and UGT2B7 to docetaxel‐TrPN. Moreover, a genetic signature of prognostic relevance for BC outcome was found. Our findings might have potential relevance for personalized management of patients with BC for prevention of treatment failure in ultrametabolizer genetic variants.
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