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Journal of Hematology & Oncology Jun 2018Bcr-Abl inhibitors paved the way of targeted therapy epoch. Imatinib was the first tyrosine kinase inhibitor to be discovered with high specificity for Bcr-Abl protein... (Review)
Review
Bcr-Abl inhibitors paved the way of targeted therapy epoch. Imatinib was the first tyrosine kinase inhibitor to be discovered with high specificity for Bcr-Abl protein resulting from t(9, 22)-derived Philadelphia chromosome. Although the specific targeting of that oncoprotein, several Bcr-Abl-dependent and Bcr-Abl-independent mechanisms of resistance to imatinib arose after becoming first-line therapy in chronic myelogenous leukemia (CML) treatment.Consequently, new specific drugs, namely dasatinib, nilotinib, bosutinib, and ponatinib, were rationally designed and approved for clinic to override resistances. Imatinib fine mechanisms of action had been elucidated to rationally develop those second- and third-generation inhibitors. Crystallographic and structure-activity relationship analysis, jointly to clinical data, were pivotal to shed light on this topic. More recently, preclinical evidence on bafetinib, rebastinib, tozasertib, danusertib, HG-7-85-01, GNF-2, and 1,3,4-thiadiazole derivatives lay promising foundations for better inhibitors to be approved for clinic in the near future.Notably, structural mechanisms of action and drug design exemplified by Bcr-Abl inhibitors have broad relevance to both break through resistances in CML treatment and develop inhibitors against other kinases as targeted chemotherapeutics.
Topics: Fusion Proteins, bcr-abl; Humans; Molecular Targeted Therapy; Protein Kinase Inhibitors; Structure-Activity Relationship; Treatment Outcome
PubMed: 29925402
DOI: 10.1186/s13045-018-0624-2 -
Blood Advances Nov 2023In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified...
In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3 × upper limit of normal, and a dual-expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.
Topics: Humans; Middle Aged; Rituximab; Retrospective Studies; Lymphoma, Large B-Cell, Diffuse; Prednisone; Vincristine; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Cyclophosphamide; Doxorubicin; Etoposide; Lactate Dehydrogenases
PubMed: 37171397
DOI: 10.1182/bloodadvances.2023009731 -
Cancer Medicine Jan 2020Aggressive non-Hodgkin lymphoma (NHL) is among the most common cancers in sub-Saharan Africa (SSA), where CHOP is standard treatment and outcomes are poor. To address...
Aggressive non-Hodgkin lymphoma (NHL) is among the most common cancers in sub-Saharan Africa (SSA), where CHOP is standard treatment and outcomes are poor. To address this, we treated 17 newly diagnosed adult patients in Malawi with Burkitt (n = 8), plasmablastic (n = 8), and primary effusion lymphoma (n = 1) with a modified EPOCH regimen between 2016 and 2019. Twelve patients (71%) were male and the median age was 40 years (range 16-63). Eleven (65%) were HIV infected, median CD4 count was 218 cells/µL (range 9-460), and nine (82%) had suppressed HIV RNA < 400 copies/mL. Patients received a median of six cycles (range 2-8) and median follow-up was 14 months (range 2-34) among patients still alive. Grade 3/4 neutropenia was observed in 26% of cycles and in 65% of patients. Sixteen (94%) responded to EPOCH and 10 (59%) achieved a complete response. One-year overall survival (OS) was 62% (95% confidence interval [CI], 42%-91%). Five patients (29%) died from progressive NHL and three (18%) from treatment-related complications. These data suggest EPOCH with setting-appropriate modifications may be a practical, safe, and effective option for improving high-risk NHL outcomes in Malawi and comparable settings, which deserves further prospective evaluation.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; CD4 Lymphocyte Count; Cyclophosphamide; Doxorubicin; Etoposide; Female; Follow-Up Studies; HIV Infections; Humans; Lymphoma, Non-Hodgkin; Malawi; Male; Middle Aged; Neutropenia; Prednisone; Progression-Free Survival; RNA, Viral; Vincristine; Young Adult
PubMed: 31705618
DOI: 10.1002/cam4.2631 -
Pediatric Research Jan 2023Child health is defined by a complex, dynamic network of genetic, cultural, nutritional, infectious, and environmental determinants at distinct, developmentally... (Review)
Review
Child health is defined by a complex, dynamic network of genetic, cultural, nutritional, infectious, and environmental determinants at distinct, developmentally determined epochs from preconception to adolescence. This network shapes the future of children, susceptibilities to adult diseases, and individual child health outcomes. Evolution selects characteristics during fetal life, infancy, childhood, and adolescence that adapt to predictable and unpredictable exposures/stresses by creating alternative developmental phenotype trajectories. While child health has improved in the United States and globally over the past 30 years, continued improvement requires access to data that fully represent the complexity of these interactions and to new analytic methods. Big Data and innovative data science methods provide tools to integrate multiple data dimensions for description of best clinical, predictive, and preventive practices, for reducing racial disparities in child health outcomes, for inclusion of patient and family input in medical assessments, and for defining individual disease risk, mechanisms, and therapies. However, leveraging these resources will require new strategies that intentionally address institutional, ethical, regulatory, cultural, technical, and systemic barriers as well as developing partnerships with children and families from diverse backgrounds that acknowledge historical sources of mistrust. We highlight existing pediatric Big Data initiatives and identify areas of future research. IMPACT: Big Data and data science can improve child health. This review highlights the importance for child health of child-specific and life course-based Big Data and data science strategies. This review provides recommendations for future pediatric-specific Big Data and data science research.
Topics: Humans; Pregnancy; Female; Child; United States; Child Health; Big Data; Data Science; Prenatal Care
PubMed: 35974162
DOI: 10.1038/s41390-022-02264-9 -
BMC Cancer Aug 2020The optimal chemotherapy regimen for treating HIV associated NHL in low resource settings is unknown. We conducted a retrospective study to describe survival rates,...
BACKGROUND
The optimal chemotherapy regimen for treating HIV associated NHL in low resource settings is unknown. We conducted a retrospective study to describe survival rates, treatment response rates and adverse events in patients with HIV associated NHL treated with CHOP and dose adjusted-EPOCH regimens at the Uganda Cancer Institute.
METHODS
A retrospective study of patients diagnosed with HIV and lymphoma and treated at the Uganda Cancer Institute from 2016 to 2018 was done.
RESULTS
One hundred eight patients treated with CHOP and 12 patients treated with DA-EPOCH were analysed. Patients completing 6 or more cycles of chemotherapy were 51 (47%) in the CHOP group and 8 (67%) in the DA-EPOCH group. One year overall survival (OS) rate in patients treated with CHOP was 54.5% (95% CI, 42.8-64.8) and 80.2% (95% CI, 40.3-94.8) in those treated with DA-EPOCH. Factors associated with favourable survival were BMI 18.5-24.9 kg/m, (p = 0.03) and completion of 6 or more cycles of chemotherapy, (p < 0.001). The overall response rate was 40% in the CHOP group and 59% in the DA-EPOCH group. Severe adverse events occurred in 19 (18%) patients in the CHOP group and 3 (25%) in the DA-EPOCH group; these were neutropenia (CHOP = 13, 12%; DA-EPOCH = 2, 17%), anaemia (CHOP = 12, 12%; DA-EPOCH = 1, 8%), thrombocytopenia (CHOP = 7, 6%; DA-EPOCH = 0), sepsis (CHOP = 1), treatment related death (DA-EPOCH = 1) and hepatic encephalopathy (CHOP = 1).
CONCLUSION
Treatment of HIV associated NHL with curative intent using CHOP and infusional DA-EPOCH is feasible in low resource settings and associated with > 50% 1 year survival.
Topics: Adult; Anemia; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Etoposide; Female; HIV Infections; Hepatic Encephalopathy; Humans; Infusions, Intravenous; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neutropenia; Prednisone; Retrospective Studies; Sepsis; Survival Rate; Thrombocytopenia; Time Factors; Treatment Outcome; Uganda; Vincristine
PubMed: 32831073
DOI: 10.1186/s12885-020-07305-2 -
British Journal of Haematology Apr 2019Primary mediastinal B-cell lymphoma (PMBCL) is a distinct disease closely related to classical nodular sclerosing Hodgkin lymphoma. Conventional diagnostic paradigms... (Review)
Review
Primary mediastinal B-cell lymphoma (PMBCL) is a distinct disease closely related to classical nodular sclerosing Hodgkin lymphoma. Conventional diagnostic paradigms utilising clinical, morphological and immunophenotypical features can be challenging due to overlapping features with other B-cell lymphomas. Reliable diagnostic and prognostic biomarkers that are applicable to the conventional diagnostic laboratory are largely lacking. Nuclear factor kappa B (NF-κB) and Janus kinase/signal transducers and activators of transcription (JAK-STAT) signalling pathways are characteristically dysregulated in PMBCL and implicated in several aspects of disease pathogenesis, and the latter pathway in host immune evasion. The tumour microenvironment is manipulated by PMBCL tumours to avoid T-cell mediated destruction via strategies that include loss of tumour cell antigenicity, T-cell exhaustion and activation of suppressive T-regulatory cells. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) and DA-EPOCH-R (dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, rituximab) are the most common first-line immunochemotherapy regimens. End of treatment positron emission tomography scans are the recommended imaging modality and are being evaluated to stratify patients for radiotherapy. Relapsed/refractory disease has a relatively poor outcome despite salvage immunochemotherapy and subsequent autologous stem cell transplantation. Novel therapies are therefore being developed for treatment-resistant disease, targeting aberrant cellular signalling and immune evasion.
Topics: Adult; Antigens, Neoplasm; Clonal Anergy; Female; Humans; Immunotherapy; Janus Kinases; Lymphoma, B-Cell; Male; Mediastinal Neoplasms; Middle Aged; NF-kappa B; STAT Transcription Factors; Signal Transduction; T-Lymphocytes; Tumor Microenvironment; Young Adult
PubMed: 30740662
DOI: 10.1111/bjh.15778 -
JAMA Network Open Apr 2023Evidence on the effectiveness and safety of COVID-19 therapies across a diverse population with varied risk factors is needed to inform clinical practice.
IMPORTANCE
Evidence on the effectiveness and safety of COVID-19 therapies across a diverse population with varied risk factors is needed to inform clinical practice.
OBJECTIVE
To assess the safety of neutralizing monoclonal antibodies (nMAbs) for the treatment of COVID-19 and their association with adverse outcomes.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study included 167 183 patients from a consortium of 4 health care systems based in California, Minnesota, Texas, and Utah. The study included nonhospitalized patients 12 years and older with a positive COVID-19 laboratory test collected between November 9, 2020, and January 31, 2022, who met at least 1 emergency use authorization criterion for risk of a poor outcome.
EXPOSURE
Four nMAb products (bamlanivimab, bamlanivimab-etesevimab, casirivimab-imdevimab, and sotrovimab) administered in the outpatient setting.
MAIN OUTCOMES AND MEASURES
Clinical and SARS-CoV-2 genomic sequence data and propensity-adjusted marginal structural models were used to assess the association between treatment with nMAbs and 4 outcomes: all-cause emergency department (ED) visits, hospitalization, death, and a composite of hospitalization or death within 14 days and 30 days of the index date (defined as the date of the first positive COVID-19 test or the date of referral). Patient index dates were categorized into 4 variant epochs: pre-Delta (November 9, 2020, to June 30, 2021), Delta (July 1 to November 30, 2021), Delta and Omicron BA.1 (December 1 to 31, 2021), and Omicron BA.1 (January 1 to 31, 2022).
RESULTS
Among 167 183 patients, the mean (SD) age was 47.0 (18.5) years; 95 669 patients (57.2%) were female at birth, 139 379 (83.4%) were White, and 138 900 (83.1%) were non-Hispanic. A total of 25 241 patients received treatment with nMAbs. Treatment with nMAbs was associated with lower odds of ED visits within 14 days (odds ratio [OR], 0.76; 95% CI, 0.68-0.85), hospitalization within 14 days (OR, 0.52; 95% CI, 0.45-0.59), and death within 30 days (OR, 0.14; 95% CI, 0.10-0.20). The association between nMAbs and reduced risk of hospitalization was stronger in unvaccinated patients (14-day hospitalization: OR, 0.51; 95% CI, 0.44-0.59), and the associations with hospitalization and death were stronger in immunocompromised patients (hospitalization within 14 days: OR, 0.31 [95% CI, 0.24-0.41]; death within 30 days: OR, 0.13 [95% CI, 0.06-0.27]). The strength of associations of nMAbs increased incrementally among patients with a greater probability of poor outcomes; for example, the ORs for hospitalization within 14 days were 0.58 (95% CI, 0.48-0.72) among those in the third (moderate) risk stratum and 0.41 (95% CI, 0.32-0.53) among those in the fifth (highest) risk stratum. The association of nMAb treatment with reduced risk of hospitalizations within 14 days was strongest during the Delta variant epoch (OR, 0.37; 95% CI, 0.31-0.43) but not during the Omicron BA.1 epoch (OR, 1.29; 95% CI, 0.68-2.47). These findings were corroborated in the subset of patients with viral genomic data. Treatment with nMAbs was associated with a significant mortality benefit in all variant epochs (pre-Delta: OR, 0.16 [95% CI, 0.08-0.33]; Delta: OR, 0.14 [95% CI, 0.09-0.22]; Delta and Omicron BA.1: OR, 0.10 [95% CI, 0.03-0.35]; and Omicron BA.1: OR, 0.13 [95% CI, 0.02-0.93]). Potential adverse drug events were identified in 38 treated patients (0.2%).
CONCLUSIONS AND RELEVANCE
In this study, nMAb treatment for COVID-19 was safe and associated with reductions in ED visits, hospitalization, and death, although it was not associated with reduced risk of hospitalization during the Omicron BA.1 epoch. These findings suggest that targeted risk stratification strategies may help optimize future nMAb treatment decisions.
Topics: Infant, Newborn; Humans; Female; Middle Aged; Male; COVID-19; SARS-CoV-2; Retrospective Studies; Antibodies, Monoclonal
PubMed: 37093599
DOI: 10.1001/jamanetworkopen.2023.9694 -
Stroke Dec 2023The Stroke Treatment Academic Industry Roundtable XII included a workshop to discuss the most promising approaches to improve outcome from acute stroke. The workshop... (Review)
Review
The Stroke Treatment Academic Industry Roundtable XII included a workshop to discuss the most promising approaches to improve outcome from acute stroke. The workshop brought together representatives from academia, industry, and government representatives. The discussion examined approaches in 4 epochs: pre-reperfusion, reperfusion, post-reperfusion, and access to acute stroke interventions. The participants identified areas of priority for developing new and existing treatments and approaches to improve stroke outcomes. Although many advances in acute stroke therapy have been achieved, more work is necessary for reperfusion therapies to benefit the most possible patients. Prioritization of promising approaches should help guide the use of resources and investigator efforts.
Topics: Humans; Brain Ischemia; Thrombolytic Therapy; Stroke; Thrombectomy; Reperfusion; Treatment Outcome
PubMed: 37886850
DOI: 10.1161/STROKEAHA.123.044279 -
Acta Neurologica Belgica Oct 2021A worldwide decline in stroke hospitalizations during the COVID-19 pandemic has been reported. Information on stroke care during the pandemic in Belgium is lacking. This...
A worldwide decline in stroke hospitalizations during the COVID-19 pandemic has been reported. Information on stroke care during the pandemic in Belgium is lacking. This study aims to analyze the impact of COVID-19 on acute stroke care in eight Belgian stroke centers. This Belgian study is part of an international observational and retrospective study in 70 countries and 457 stroke centers. We compared volumes of COVID-19 and stroke hospitalizations, intravenous thrombolysis and endovascular treatment rates, acute treatment time intervals and functional outcome at 90 days during the first wave of the pandemic to two control intervals (March-May 2019 and December-February 2020). From March 2020 to May 2020, 860 stroke patients were hospitalized. In the same time period, 2850 COVID-19 patients were admitted, of which 37 (1.3%) were diagnosed with a stroke. Compared to the months prior to the pandemic and the same time epoch one year earlier, stroke hospitalizations were reduced (relative difference 15.9% [p = 0.03] and 14.5% [p = 0.05], respectively). Despite a reduction in absolute volumes, there was no difference in the monthly proportion of thrombolysis or endovascular treatment provided to the overall stroke hospitalizations. Acute treatment time metrics did not change between COVID-19 pandemic and control time epochs. We found no difference in 90-day functional outcomes nor in mortality after stroke between patients admitted during the pandemic versus control periods. We found a decline in the volume of stroke hospitalizations during the first wave of the COVID-19 pandemic in Belgium. Stroke care quality parameters remained unchanged.
Topics: Belgium; COVID-19; Humans; SARS-CoV-2; Stroke
PubMed: 34148220
DOI: 10.1007/s13760-021-01726-x -
Epilepsia Oct 2021There is a paucity of data to guide anterior nucleus of the thalamus (ANT) deep brain stimulation (DBS) with brain sensing. The clinical Medtronic Percept DBS device...
There is a paucity of data to guide anterior nucleus of the thalamus (ANT) deep brain stimulation (DBS) with brain sensing. The clinical Medtronic Percept DBS device provides constrained brain sensing power within a frequency band (power-in-band [PIB]), recorded in 10-min averaged increments. Here, four patients with temporal lobe epilepsy were implanted with an investigational device providing full bandwidth chronic intracranial electroencephalogram (cEEG) from bilateral ANT and hippocampus (Hc). ANT PIB-based seizure detection was assessed. Detection parameters were cEEG PIB center frequency, bandwidth, and epoch duration. Performance was evaluated against epileptologist-confirmed Hc seizures, and assessed by area under the precision-recall curve (PR-AUC). Data included 99 days of cEEG, and 20, 278, 3, and 18 Hc seizures for Subjects 1-4. The best detector had 7-Hz center frequency, 5-Hz band width, and 10-s epoch duration (group PR-AUC = .90), with 75% sensitivity and .38 false alarms per day for Subject 1, and 100% and .0 for Subjects 3 and 4. Hc seizures in Subject 2 did not propagate to ANT. The relative change of ANT PIB was maximal ipsilateral to seizure onset for all detected seizures. Chronic ANT and Hc recordings provide direct guidance for ANT DBS with brain sensing.
Topics: Anterior Thalamic Nuclei; Deep Brain Stimulation; Epilepsy; Hippocampus; Humans; Seizures; Thalamus
PubMed: 34418083
DOI: 10.1111/epi.17047