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2021 ◽  
Vol 11 ◽  
Author(s):  
Axel Cailleteau ◽  
Paul Sargos ◽  
Fred Saad ◽  
Igor Latorzeff ◽  
Stéphane Supiot

Although salvage prostate bed radiotherapy is highly effective in biochemically-relapsing prostate cancer patients following prostatectomy, relapses remain frequent and improvements are needed. Randomized phase 3 trials have shown the benefit of adding androgen-depriving therapy to irradiation, but not all patients benefit from this combination. Preclinical studies have shown that novel agents targeting the androgen receptor, DNA repair, PI3K/AKT/mTOR pathways, or the hypoxic microenvironment may help increase the response to prostate bed irradiation while minimizing potential side effects. This perspective review focuses on the most relevant molecules that may have an impact when combined with salvage radiotherapy, and underlines the strategies that need to be developed to increase the efficacy of salvage post-prostatectomy radiotherapy in prostate cancer patients.


2021 ◽  
Author(s):  
Zaki Al-Yafeai ◽  
Anil Ananthaneni ◽  
Mohamed Ghoweba ◽  
Hamzah Abduljabar ◽  
David Aziz

Background: Multiple myeloma accounts for over 15% of hematological malignancies. In attempt to tackle this malady, the FDA approved four drugs in 2015 which has propagated further development of new anti-multiple myeloma since. However, the health safety of these new agents is still ill-defined. The aim of this study is to delineate the cardiovascular adverse events of these drugs. Methods: We searched the cardiac adverse events of the newly approved FDA drugs since 2015 using the U.S. Food and Drug Administration Adverse Events Reporting System database. We calculated the reporting odds ratio (ROR) with 95% confidence for four drugs that have the highest incidence of cardiovascular adverse events. Results: Between 2015-2020, the FDA approved six novel agents for multiple myeloma which includes elotuzumab, Ixazomib, daratumumab, panobinostat, Isatuximab, and belantamab mafodotin. Among all these medications, elotuzumab, Ixazomib, daratumumab, and panobinostat showed the highest incidence of cardiovascular complications. After vetting all the cardiac adverse events, our analysis revealed that atrial fibrillation, heart failure, and coronary disease were the highest reported cardiac events with significant odds ratio. Conclusions: The newly approved multiple myeloma therapy (elotuzumab, Ixazomib, daratumumab, panobinostat) are significantly associated with cardiotoxicity. These results highlight the importance of considering the cardiac history of patients with multiple myeloma when utilizing these novel agents.


2021 ◽  
Vol 28 (6) ◽  
pp. 5480-5498
Author(s):  
Mostafa F. Mohammed Saleh ◽  
Ahmed Kotb ◽  
Ghada E. M. Abdallah ◽  
Ibrahim N. Muhsen ◽  
Riad El Fakih ◽  
...  

Angioimmunoblastic T cell lymphoma (AITL) is a common subtype of mature peripheral T cell lymphoma (PTCL). As per the 2016 World Health Organization classification, AITL is now considered as a subtype of nodal T cell lymphoma with follicular helper T cells. The diagnosis is challenging and requires a constellation of clinical, laboratory and histopathological findings. Significant progress in the molecular pathophysiology of AITL has been achieved in the past two decades. Characteristic genomic features have been recognized that could provide a potential platform for better diagnosis and future prognostic models. Frontline therapy for AITL was mainly depending on chemotherapy and the management of relapsed or refractory AITL is still unsatisfactory with a very poor prognosis. Upfront transplantation offers better survival. Novel agents have been introduced recently with promising outcomes. Several clinical trials of combinations using novel agents are underway. Herein, we briefly review recent advances in AITL diagnosis and the evolving treatment landscape.


Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3464
Author(s):  
Nicholas Nikesitch ◽  
Patricia Rebeiro ◽  
Lye Lin Ho ◽  
Srinivasa Pothula ◽  
Xin Maggie Wang ◽  
...  

Background: Multiple myeloma (MM) remains incurable despite high-dose chemotherapy, autologous stem cell transplants and novel agents. Even with the improved survival of MM patients treated with novel agents, including bortezomib (Bz), the therapeutic options in relapsed/refractory MM remain limited. The majority of MM patients eventually develop resistance to Bz, although the mechanisms of the resistance are poorly understood. Methods: Lysosomal associated membrane protein 2A (LAMP2A) mRNA and protein expression levels were assessed in ex vivo patient samples and a Bz-resistant MM cell line model by in real-rime PCR, western blotting and immunohistochemistry. In vitro modelling of chaperone-mediated autophagy (CMA) activity in response to ER stress were assessed by western blotting and confocal microscopy. The effects of CMA inhibition on MM cell viability and Bz sensitivity in MM cells were assessed by Annexin V/7AAD apoptosis assays using flow cytometry. Results: In this study, there is evidence that CMA, a chaperone-mediated protein degradation pathway, is upregulated in Bz-resistant MM and the inhibition of CMA sensitises resistant cells to Bz. The protein levels of LAMP2A, the rate-limiting factor of the CMA pathway, are significantly increased in MM patients resistant to Bz and within our Bz-resistant cell line model. Bz-resistant cell lines also possessed higher basal CMA activity than the Bz-sensitive parent cell line. In MM cell lines, CMA activity was upregulated in response to ER stress induced by Bz. The inhibition of CMA sensitises Bz-resistant cells to Bz and the combination of CMA inhibition and Bz in vitro had a more cytotoxic effect on myeloma cells than Bz alone. Conclusion: In summary, the upregulation of CMA is a potential mechanism of resistance to Bz and a novel target to overcome Bz-resistant MM.


2021 ◽  
Author(s):  
I. Turchin ◽  
M. Kirillin ◽  
A. Orlova ◽  
V. Perekatova ◽  
V. Plekhanov ◽  
...  
Keyword(s):  

2021 ◽  
Author(s):  
Yufeng Shang ◽  
Yanxia Jin ◽  
Hailing Liu ◽  
Lu Ding ◽  
Xiqin Tong ◽  
...  

2021 ◽  
Vol 11 (12) ◽  
Author(s):  
Ryan J. Stubbins ◽  
Aly Karsan

AbstractBlocked cellular differentiation is a central pathologic feature of the myeloid malignancies, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Treatment regimens promoting differentiation have resulted in incredible cure rates in certain AML subtypes, such as acute promyelocytic leukemia. Over the past several years, we have seen many new therapies for MDS/AML enter clinical practice, including epigenetic therapies (e.g., 5-azacitidine), isocitrate dehydrogenase (IDH) inhibitors, fms-like kinase 3 (FLT3) inhibitors, and lenalidomide for deletion 5q (del5q) MDS. Despite not being developed with the intent of manipulating differentiation, induction of differentiation is a major mechanism by which several of these novel agents function. In this review, we examine the new therapeutic landscape for these diseases, focusing on the role of hematopoietic differentiation and the impact of inflammation and aging. We review how current therapies in MDS/AML promote differentiation as a part of their therapeutic effect, and the cellular mechanisms by which this occurs. We then outline potential novel avenues to achieve differentiation in the myeloid malignancies for therapeutic purposes. This emerging body of knowledge about the importance of relieving differentiation blockade with anti-neoplastic therapies is important to understand how current novel agents function and may open avenues to developing new treatments that explicitly target cellular differentiation. Moving beyond cytotoxic agents has the potential to open new and unexpected avenues in the treatment of myeloid malignancies, hopefully providing more efficacy with reduced toxicity.


2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. e002135
Author(s):  
Jordan Gemelas ◽  
Miguel Marino ◽  
Steele Valenzuela ◽  
Teresa Schmidt ◽  
Andrew Suchocki ◽  
...  

IntroductionMost patients with diabetes mellitus are prescribed medications to control their blood glucose. The implementation of the Affordable Care Act (ACA) led to improved access to healthcare for patients with diabetes. However, impact of the ACA on prescribing trends by diabetes drug category is less clear. This study aims to assess if long-acting insulin and novel agents were prescribed more frequently following the ACA in states that expanded Medicaid compared with non-expansion states.Research design and methodsIn this analysis of a natural experiment, prescriptions reimbursed by Medicaid (US public insurance) for long-acting insulins, metformin, and novel agent medications (DPP4 inhibitors, sodium/glucose cotransporter 2 inhibitor antagonists, and glucagon-like peptide-1 receptor agonists) from 2012 to 2017 were obtained from public records. For each medication category, we performed difference-in-differences (DID) analysis modeling change in rate level from pre-ACA to post-ACA in Medicaid expansion states relative to Medicaid non-expansion states.ResultsExpansion and non-expansion states saw a decline in both metformin and long-acting insulin prescriptions per 100 enrollees from pre-ACA to post-ACA. These decreases were larger in non-expansion states relative to expansion states (metformin: absolute DID = +0.33, 95% CI=0.323 to 0.344) and long-acting insulin (absolute DID: +0.11; 95% CI=0.098 to 0.113). Novel agent prescriptions in expansion states (+0.08 per 100 enrollees) saw a higher absolute increase per 100 Medicaid enrollees than in non-expansion states (absolute DID= +0.08, 95% CI=0.079 to 0.086).ConclusionsThere was a greater absolute increase for prescriptions of novel agents in expansion states relative to non-expansion states after accounting for number of enrollees. Reducing administrative barriers and improving the ability of providers to prescribe such newer therapies will be critical for caring for patients with diabetes—particularly in Medicaid non-expansion states.


2021 ◽  
pp. 1-8
Author(s):  
Harsh Shah ◽  
Hyejeong Jang ◽  
Paramveer Singh ◽  
Jorgena Kosti ◽  
Andrew Kin ◽  
...  

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5606
Author(s):  
Maarten R. Seefat ◽  
David G. J. Cucchi ◽  
Stijn Dirven ◽  
Kaz Groen ◽  
Sonja Zweegman ◽  
...  

Background: Novel therapies for multiple myeloma (MM) promise to improve outcomes but are also associated with substantial increasing costs. Evidence regarding cost-effectiveness of novel treatments is necessary, but a comprehensive up-to-date overview of the cost-effectiveness evidence of novel treatments is currently lacking. Methods: We searched Embase, Medline via Ovid, Web of Science and EconLIT ProQuest to identify all cost-effectiveness evaluations of novel pharmacological treatment of MM reporting cost per quality-adjusted life year (QALY) and cost per life year (LY) gained since 2005. Quality and completeness of reporting was assessed using the Consolidated Health Economic Evaluation Reporting Standards. Results: We identified 13 economic evaluations, comprising 32 comparisons. Our results show that novel agents generate additional LYs (range: 0.311–3.85) and QALYs (range: 0.1–2.85) compared to backbone regimens and 0.02 to 1.10 LYs and 0.01 to 0.91 QALYs for comparisons between regimens containing two novel agents. Lifetime healthcare costs ranged from USD 60,413 to 1,434,937 per patient. The cost-effectiveness ratios per QALY gained ranged from dominating to USD 1,369,062 for novel agents compared with backbone therapies and from dominating to USD 618,018 for comparisons between novel agents. Conclusions: Cost-effectiveness ratios of novel agents were generally above current willingness-to-pay thresholds. To ensure access, cost-effectiveness should be improved or cost-effectiveness ratios above current thresholds should be accepted.


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