Substantial loss of intrahepatic HBV cccDNA during antiviral combination therapy translates into long-term clinical benefit

SummaryVenous thrombosis is a chronic disease with a recurrence rate of approximately 30% within 5-8 years. The optimal duration of secondary thromboprophylaxis in these patients entails balancing the risk of recurrence against the risk of treatment-associated bleeding. There is agreement that patients with a first idiopathic venous thrombosis should receive vitamin K antagonists for at least 3-6 months. Convincing trials showing a clinical benefit in terms of morbidity or mortality with respect to expansion of anticoagulation beyond 6 months are lacking. Nevertheless, some subgroups of patients with venous thrombosis may benefit from indefinite anticoagulation. Thus, patients with antithrombin deficiency, combined or homozygous defects, more than one unprovoked episode of thrombosis, the lupus anticoagulant or high factor VIII plasma levels are good candidates for long-term prevention.

Download Full-text

Drug Combinatorial Therapies for the Treatment of KRAS Mutated Lung Cancers

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190902150555 ◽

2019 ◽

Vol 19 (23) ◽

pp. 2128-2142 ◽

Cited By ~ 2

Author(s):

Hao He ◽

Chang Xu ◽

Zhao Cheng ◽

Xiaoying Qian ◽

Lei Zheng

Keyword(s):

Lung Cancer ◽

Adjuvant Therapy ◽

Combination Therapy ◽

Clinical Benefit ◽

Poor Prognosis ◽

Egfr Mutations ◽

Kras Mutations ◽

Lung Cancers ◽

Egfr Tki ◽

Egfr Tkis

: KRAS is the most common oncogene to be mutated in lung cancer, and therapeutics directly targeting KRAS have proven to be challenging. The mutations of KRAS are associated with poor prognosis, and resistance to both adjuvant therapy and targeted EGFR TKI. EGFR TKIs provide significant clinical benefit for patients whose tumors bear EGFR mutations. However, tumors with KRAS mutations rarely respond to the EGFR TKI therapy. Thus, combination therapy is essential for the treatment of lung cancers with KRAS mutations. EGFR TKI combined with inhibitors of MAPKs, PI3K/mTOR, HDAC, Wee1, PARP, CDK and Hsp90, even miRNAs and immunotherapy, were reviewed. Although the effects of the combination vary, the combined therapeutics are one of the best options at present to treat KRAS mutant lung cancer.

Download Full-text

Correction to: Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial

Annals of Hematology ◽

10.1007/s00277-021-04545-5 ◽

2021 ◽

Author(s):

Michael Heuser ◽

B. Douglas Smith ◽

Walter Fiedler ◽

Mikkael A. Sekeres ◽

Pau Montesinos ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Clinical Benefit ◽

Myeloid Leukemia ◽

Low Dose ◽

De Novo ◽

Secondary Acute Myeloid Leukemia ◽

Term Analysis ◽

Low Dose Cytarabine ◽

Acute Myeloid

Download Full-text

Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial

Annals of Hematology ◽

10.1007/s00277-021-04465-4 ◽

2021 ◽

Author(s):

Michael Heuser ◽

B. Douglas Smith ◽

Walter Fiedler ◽

Mikkael A. Sekeres ◽

Pau Montesinos ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Phase Ii ◽

Clinical Benefit ◽

Myeloid Leukemia ◽

Low Dose ◽

De Novo ◽

Secondary Acute Myeloid Leukemia ◽

Low Dose Cytarabine ◽

Acute Myeloid

AbstractThis analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325–0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395–1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151–0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days’ therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.

Download Full-text

Hepatitis B Core-Related Antigen as Surrogate Biomarker of Intrahepatic Hepatitis B Virus Covalently-Closed-Circular DNA in Patients with Chronic Hepatitis B: A Meta-Analysis

Diagnostics ◽

10.3390/diagnostics11020187 ◽

2021 ◽

Vol 11 (2) ◽

pp. 187

Author(s):

Gian Paolo Caviglia ◽

Angelo Armandi ◽

Chiara Rosso ◽

Davide Giuseppe Ribaldone ◽

Rinaldo Pellicano ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Hepatitis B Surface Antigen ◽

Meta Analysis ◽

Circular Dna ◽

Non Invasive ◽

Hbv Cccdna ◽

B Virus ◽

Chronic Hbv ◽

Intrahepatic Hbv

Hepatitis B virus (HBV) covalently-closed-circular (ccc)DNA is the key molecule responsible for viral persistence within infected hepatocytes. The evaluation of HBV cccDNA is crucial for the management of patients with chronic HBV infection and for the personalization of treatment. However, the need for liver biopsy is the principal obstacle for the assessment of intrahepatic HBV cccDNA. In the last decade, several studies have investigated the performance of hepatitis B core-related antigen (HBcrAg) as a surrogate of HBV cccDNA amount in the liver. In this meta-analysis, we collected 14 studies (1271 patients) investigating the correlation between serum HBcrAg and intrahepatic HBV cccDNA. Serum HBcrAg showed a high correlation with intrahepatic HBV cccDNA (r = 0.641, 95% confidence interval (CI) 0.510–0.743, p < 0.001). In a head-to-head comparison, we observed that the performance of HBcrAg was significantly superior to that of hepatitis B surface antigen (r = 0.665 vs. r = 0.475, respectively, p < 0.001). Subgroup analysis showed that the correlation between HBcrAg and intrahepatic HBV cccDNA was high, both in hepatitis B e antigen-positive and -negative patients (r = 0.678, 95% CI 0.403–0.840, p < 0.001, and r = 0.578, 95% CI 0.344–0.744, p < 0.001, respectively). In conclusion, the measurement of serum HBcrAg qualifies as a reliable non-invasive surrogate for the assessment of an intrahepatic HBV cccDNA reservoir.

Download Full-text