scholarly journals PO-1916 Low-dose lung radiotherapy for COVID-19 pneumonia: preclinical studies in bleomycin pneumonitis

2021 ◽  
Vol 161 ◽  
pp. S1633-S1635
Author(s):  
A. Chalmers ◽  
M. Jackson ◽  
K. Stevenson ◽  
S. Chahal ◽  
E. Curley ◽  
...  
2021 ◽  
pp. 106531
Author(s):  
Sweety Gupta ◽  
Rachit Ahuja ◽  
Nidhi Sharma ◽  
Pragya Singh ◽  
Swati Verma ◽  
...  

2020 ◽  
Vol 32 (8) ◽  
pp. 497-500 ◽  
Author(s):  
H. Tharmalingam ◽  
P. Díez ◽  
Y. Tsang ◽  
A. Hawksley ◽  
J. Conibear ◽  
...  

2020 ◽  
Author(s):  
Nam Nguyen ◽  
Meritxell Arenas ◽  
Te Vuong ◽  
Alice Zamagni ◽  
Vincent Vinh-Hung ◽  
...  

BACKGROUND Coronavirus disease 19 (COVID-19) carry a high mortality rate among older patients and minorities such as ethnic Africans and Latinos. The chronic baseline systemic inflammation of older patients and minorities may make them more vulnerable to the cytokines storm generated by the viral infection in addition to preexisting co-morbidity. Even though multiple organs failure result from the cytokine storm, pneumonia and respiratory failure often lead to death. OBJECTIVE Low dose whole lung radiotherapy (LDWLRT) may modulate the inflammatory response and may decrease the need for artificial ventilation, thus improving mortality rate. METHODS A phase I-II prospective trials enrolling 500 patients, 65 years old or older from 25 countries will be conducted to investigate the impact of LDWLRT on mortality rate of COVID-19 patients. The patients who will be selected would have developed pneumonias but did not require artificial ventilation. These patients will be followed for a year after receiving this treatment. Their physical activities will be monitored through the ordinal scale and will be correlated with their cytokines status and oxygen saturation rate to assess the impact of the residual inflammation on their daily life. Mortality rates between different ethnic group will be compared and correlated with their cytokines response to the virus and number of co-morbidities. RESULTS We postulate that LDWLRT may improve survival rates of all patients by preventing the need for artificial ventilation which is associated with a high mortality. The inflammatory response between different ethnic groups before and following radiotherapy will be valuable to serve as baseline for future prospective pandemic studies as it has not been reported before. CONCLUSIONS Once the study is complete, we may be able to demonstrate that LDWLRT may improve survival through its anti-inflammatory property CLINICALTRIAL NCT 04493294


2021 ◽  
Author(s):  
Mark R Jackson ◽  
Katrina Stevenson ◽  
Sandeep K Chahal ◽  
Emer Curley ◽  
George E Finney ◽  
...  

AbstractPurposeLow-dose whole lung radiotherapy (LDLR) has been proposed as a treatment for patients with acute respiratory distress syndrome associated with SARS-CoV-2 infection and clinical trials are underway. There is an urgent need for preclinical evidence to justify this approach and inform dose, scheduling and mechanisms of action.Materials and methodsFemale C57BL/6 mice were treated with intranasal bleomycin sulphate (7.5 or 11.25 units/kg, day 0), then exposed to whole lung radiation therapy (0.5, 1.0, 1.5 Gy or sham, day 3). Bodyweight was measured daily and lung tissue harvested for histology and flow cytometry on day 10. Computed tomography (CT) lung imaging was performed pre-radiation (day 3) and pre-endpoint (day 10).ResultsBleomycin caused pneumonitis of variable severity which correlated with weight loss. LDLR at 1.0 Gy was associated with a significant increase in the proportion of mice recovering to 98% of initial bodyweight and a proportion of these mice exhibited less severe histopathological lung changes. Mice experiencing moderate initial weight loss were more likely to respond to LDLR than those experiencing severe initial weight loss. Additionally, LDLR (1.0 Gy) significantly reduced bleomycin-induced increases in interstitial macrophages, CD103+ dendritic cells and neutrophil-DC hybrids. Overall,bleomycin-treated mice exhibited significantly higher percentages of non-aerated lung in left than right lungs and LDLR (1.0 Gy) prevented further reductions in aerated lung volume in right but not left lungs. LDLR at 0.5 and 1.5 Gy did not modulate bodyweight or flow cytometric readouts of bleomycin-induced pneumonitis.ConclusionsOur data support the concept that LDLR can ameliorate acute inflammatory lung injury, identify 1.0 Gy as the most effective dose and provide preliminary evidence that it is more effective in the context of moderate than severe pneumonitis. Mechanistically, LDLR at 1.0 Gy significantly suppressed bleomycin-induced accumulation of pulmonary interstitial macrophages, CD103+ dendritic cells and neutrophil-DC hybrids.


2021 ◽  
Vol 33 (1) ◽  
pp. e64-e68
Author(s):  
D. Hadjiyiannakis ◽  
D. Dimitroyannis ◽  
L. Eastlake ◽  
C. Peedell ◽  
L. Tripathi ◽  
...  

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4034-4034 ◽  
Author(s):  
David Gomez-Almaguer ◽  
Roxana Saldaña-Vázquez ◽  
Olga Graciela Cantú-Rodríguez ◽  
Cesar H Gutiérrez-Aguirre ◽  
Jose Carlos Jaime-Pérez ◽  
...  

Abstract Introduction Introduction of tyrosine kinase inhibitors (TKI) as first-line therapy has reduced mortality related to CML in the last 10 years. According to IRIS study probability of maintaining CCyR to 5 years with imatinib is 63%. Therefore 30-35% of patients will require alternative treatment for primary, secondary resistance or intolerance to treatment. Nilotinib has shown to be 20 times more potent than imatinib in cells expressing unmutated BCR / ABL and is effective against up to 30 different mutations present in the imatinib resistant patient. It now has a role as first line CML therapy or second line in the case of imatinib failure. Drug combinations are common in the treatment of other neoplasms, preclinical studies showed that nilotinib has a synergistic effect when used in conjunction with imatinib, for inducing apoptosis and decreases cell proliferation without relevant toxicity. Combination of these two drugs has been used in the treatment of gastrointestinal stromal tumor (GIST) and in at least 2 reported cases of CML, with good results and without increased toxicity. Low-dose nilotinib in combination with low-dose imatinib appears to be another option for patients with failure, suboptimal response or intolerance to imatinib therapy. In this pilot and prospective study, we analyzed the effectiveness and tolerability of this combination. Objective To evaluate cytogenetic and molecular response to low-dose imatinib and nilotinib combined treatment in CML patients with failure, suboptimal response or intolerance to imatinib therapy and the potential toxicity of the combination. Methods CML patients with failure, suboptimal response or intolerance to imatinib therapy were evaluated. Cytogenetic analysis, quantitative PCR for BCR/ABL and evaluation for mutations were performed at baseline. All patients received treatment as follows: imatinib 200 mg daily and nilotinib 300 mg daily for 6 months. Quantitative PCR for BCR/ABL was performed at 3 months, and cytogenetic analysis and quantitative PCR for BCR/ABL at 6 months. If hematologic progression occurred, stepwise dose escalation of imatinib 200 mg and nilotinib 150-300 mg monthly was permitted until a maximum dose of 800 or 750 mg each. Kolmogorov-Smirnov was use to test for normality, T-test, Friedman test and Q Cochran were used for parametric and non parametric variables respectively. Results Ten patients were included, 6 men and 4 women, median age of 38 years (27-68). Median time from diagnosis was 65.8 (13.7-149.3) months, and time of previous imatinib treatment was 60.8 (30.0-113.3) months; with a median imatinib dose of 400 mg (400-800), 80% had treatment failure and 20% suboptimal response according to European Leukemia Net criteria. No patients with treatment intolerance were included. Mutations were detected in 40% of patients. At baseline only 2 patients had complete cytogenetic response, at 6 months 6 patients had complete cytogenetic response (p=0.046), at 6 months 40% of patients had achieved major molecular response (p=0.039). Mean percentage of BCR/ABL transcripts detected by quantitative PCR before treatment and at 3 and 6 months was 15.62% IS (SD±18.39), 7.25% IS (SD± 8.48) and 1.05% IS (SD± 1.32) respectively, with a significant difference, p= 0.045. The most frequent side effect was rash in 4 patients; with mild severity and complete response to antihistaminic treatment in all cases. One patient had to be withdrawn from the study after 3 months of treatment because of grade 4 thrombocytopenia. None of the patients presented disease progression. Conclusion Our results support the information that preclinical studies showed, that nilotinib has a synergistic effect when used in conjunction with imatinib. Low-dose imatinib and nilotinib combination is an effective and safe treatment alternative for some patients with failure, suboptimal response or intolerance to imatinib monotherapy at standard dose. Disclosures: Off Label Use: Nilotinib and imatinib at low dose.


Author(s):  
T. M. Seed ◽  
M. H. Sanderson ◽  
D. L. Gutzeit ◽  
T. E. Fritz ◽  
D. V. Tolle ◽  
...  

The developing mammalian fetus is thought to be highly sensitive to ionizing radiation. However, dose, dose-rate relationships are not well established, especially the long term effects of protracted, low-dose exposure. A previous report (1) has indicated that bred beagle bitches exposed to daily doses of 5 to 35 R 60Co gamma rays throughout gestation can produce viable, seemingly normal offspring. Puppies irradiated in utero are distinguishable from controls only by their smaller size, dental abnormalities, and, in adulthood, by their inability to bear young.We report here our preliminary microscopic evaluation of ovarian pathology in young pups continuously irradiated throughout gestation at daily (22 h/day) dose rates of either 0.4, 1.0, 2.5, or 5.0 R/day of gamma rays from an attenuated 60Co source. Pups from non-irradiated bitches served as controls. Experimental animals were evaluated clinically and hematologically (control + 5.0 R/day pups) at regular intervals.


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