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American Journal of Hematology May 2022The field of mantle cell lymphoma (MCL) has witnessed remarkable progress due to relentless advances in molecular pathogenesis, prognostication, and newer treatments....
The field of mantle cell lymphoma (MCL) has witnessed remarkable progress due to relentless advances in molecular pathogenesis, prognostication, and newer treatments. MCL consists of a spectrum of clinical subtypes. Rarely, atypical cyclin D1-negative MCL and in situ MCL neoplasia are identified. Prognostication of MCL is further refined by identifying somatic mutations (such as TP53, NSD2, KMT2D), methylation status, chromatin organization pattern, SOX-11 expression, minimal residual disease (MRD), and genomic clusters. Lymphoid tissue microenvironment studies demonstrated the role of B-cell receptor signaling, nuclear factor kappa B (NF-kB), colony-stimulating factor (CSF)-1, the CD70-SOX-11 axis. Molecular mechanism of resistance, mutation dynamics, and pathogenic pathways (B-cell receptor (BCR), oxidative phosphorylation, and MYC) were identified in mediating resistance to various treatments (bruton tyrosine kinase (BTK) inhibitors [ibrutinib, acalabrutinib]. Treatment options range from conventional chemoimmunotherapy and stem cell transplantation (SCT) to targeted therapies against BTK (covalent and noncovalent), Bcl2, ROR1, cellular therapy such as anti-CD19 chimeric antigen receptor therapy (CAR-T), and most recently bispecific antibodies against CD19 and CD20. MCL patients frequently relapse. Complex pathogenesis and the management of patients with progression after treatment with BTK/Bcl2 inhibitors and CAR-T (triple-resistant MCL) remain a challenge. Next-generation clinical trials incorporating newer agents and concurrent translational and molecular investigations are ongoing.
Topics: Adult; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Risk Assessment; Tumor Microenvironment
PubMed: 35266562
DOI: 10.1002/ajh.26523 -
American Journal of Hematology Jun 2019Unprecedented advances in our understanding of the pathobiology, prognostication, and therapeutic options in mantle cell lymphoma (MCL) have taken place in the last few... (Review)
Review
Unprecedented advances in our understanding of the pathobiology, prognostication, and therapeutic options in mantle cell lymphoma (MCL) have taken place in the last few years. Heterogeneity in the clinical course of MCL-indolent vs aggressive-is further delineated by a correlation with the mutational status of the variable region of immunoglobulin heavy chain, methylation status, and SOX-11 expression. Cyclin-D1 negative MCL, in situ MCL neoplasia, and impact of the karyotype on prognosis are distinguished. Apart from Ki-67% and morphology pattern (classic vs blastoid/pleomorphic), the proliferation gene signature has helped to further refine prognostication. Studies focusing on mutational dynamics and clonal evolution on Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib) and/or Bcl2 antagonists (venetoclax) have further clarified the prognostic impact of somatic mutations in TP53, BIRC3, CDKN2A, MAP3K14, NOTCH2, NSD2, and SMARCA4 genes. In therapy, long-term follow-up on chemo-immunotherapy studies has demonstrated durable remissions in some patients; however, long-term toxicities, especially from second cancers, are a serious concern with chemotherapy. The therapeutic options in MCL are constantly evolving, with dramatic responses from nonchemotherapeutic agents (ibrutinib, acalabrutinib, and venetoclax). Chimeric antigen receptor therapy and combinations of nonchemotherapeutic agents are actively being studied and our focus is shifting toward making the treatment of MCL chemotherapy-free. Still, MCL remains incurable. The following aspects of MCL continue to pose a challenge: disease transformation, role of the cytokine-microenvironmental milieu, incorporation of positron emission tomography-computerized tomography imaging, minimal residual disease in the prognosis, circulating tumor DNA testing for clonal evolution, predicting resistance to BTK inhibitors, and optimal management of patients who progress on BTK/Bcl2 inhibitors. Next-generation clinical trials should incorporate nonchemotherapeutic agents and personalize the treatment based upon the genomic profile of individual patient. Recent advances in the field of MCL are reviewed.
Topics: Antineoplastic Agents; Disease-Free Survival; Humans; Lymphoma, Mantle-Cell; Neoplasm Proteins; Survival Rate
PubMed: 30963600
DOI: 10.1002/ajh.25487 -
European Heart Journal. Case Reports Jan 2022Mantle field radiotherapy has been known to cause cardiovascular complications even years after therapy. Complications include pericardial disease, coronary artery...
BACKGROUND
Mantle field radiotherapy has been known to cause cardiovascular complications even years after therapy. Complications include pericardial disease, coronary artery disease, and conduction abnormalities.
CASE SUMMARY
We present a case series of two patients who developed cardiovascular complications years after receiving mantle radiation. Patient 1 is a 52-year-old man who presented with symptoms of heart failure. He had a neurostimulator which precluded him from cardiac magnetic resonance imaging. Haemodynamic findings on right heart catheterization raised suspicion for constrictive pericarditis and pericardiectomy was performed. Histopathological analysis reported dense, sclerotic fibrous tissue consistent with radiation-related changes. Patient 2 is a 37-year-old man with a 2-month history of chest pain and exertional dyspnoea who was admitted for management of coronary artery disease. Coronary angiography demonstrated bilateral subclavian artery stenosis and an elevated left ventricular end-diastolic pressure (50 mmHg). He had bilateral percutaneous subclavian artery stenting. Both patients had complete resolution of symptoms on follow-up.
DISCUSSION
Our case series emphasizes the need for an index of suspicion for radiation-related cardiovascular changes in patients who have a history of mantle radiation, especially in younger patients. This was especially pertinent in the case of our first patient who presented a diagnostic challenge due to certain patient factors. Our second patient is a case of subclavian artery stenosis which is less frequently reported as a complication of mantle radiation in the literature.
PubMed: 35174307
DOI: 10.1093/ehjcr/ytac017 -
Expert Review of Anticancer Therapy Jun 2017Mantle cell lymphoma (MCL) usually takes an aggressive clinical course and carries a poor prognosis. Recently, progress has been made in the treatment of MCL including... (Review)
Review
Mantle cell lymphoma (MCL) usually takes an aggressive clinical course and carries a poor prognosis. Recently, progress has been made in the treatment of MCL including the development of a number of novel agents which target intracellular pathways and the extracellular microenvironment. These agents have transformed the landscape of available therapeutic options. Areas covered: The current literature on the novel agents which currently hold a licence for the treatment of MCL in the context of front-line therapy and in the relapsed/refractory setting is summarized. In addition, targeted therapies showing promise at an earlier stage of development will also be discussed. A literature search was performed using the terms 'mantle cell lymphoma', 'bortezomib', 'temsirolimus', 'lenalidomide', 'ibrutinib', 'novel agents', 'targeted molecular therapies' and derivations thereof. Expert commentary: In addition to improvements in immunochemotherapy, a succession of new molecular targets and corresponding drugs has revolutionised MCL therapy. The discovery of a novel agent which disrupts external signalling pathways through inhibition of Bruton's tyrosine kinase has been a particularly exciting breakthrough. The best way to sequence and combine these agents with existing regimens and how to overcome the problem of drug resistance represent new challenges in this rapidly developing field.
Topics: Animals; Antineoplastic Agents; Drug Design; Drug Resistance, Neoplasm; Humans; Immunotherapy; Lymphoma, Mantle-Cell; Molecular Targeted Therapy; Prognosis; Signal Transduction; Tumor Microenvironment
PubMed: 28480764
DOI: 10.1080/14737140.2017.1328280 -
Journal of Plastic, Reconstructive &... Jan 2022Mastectomy may be needed in the context of previous radiotherapy in cases of breast carcinoma following mantle field radiotherapy for Hodgkin lymphoma or in cases of...
Combined skin-sparing mastectomy and immediate implant-based breast reconstruction: Outcome following mantle field irradiation versus outcome following whole-breast irradiation.
BACKGROUND
Mastectomy may be needed in the context of previous radiotherapy in cases of breast carcinoma following mantle field radiotherapy for Hodgkin lymphoma or in cases of local relapse or second primary tumours after breast conserving therapy including whole-breast irradiation (BCT). The outcome of combined skin-sparing mastectomy and immediate implant-based breast reconstruction (SSM-IIBR) has been reported to be unfavourable in these cases.
PURPOSE
To compare the outcome of SSM-IIBR after mantle field radiotherapy to that after BCT and to compare both to the outcome observed in non-irradiated breasts.
METHODOLOGY
The prevalences of short-term events, device loss, long-term corrections and secondary reconstructions, and reversion to autologous tissue techniques of 42 SSM-IIBRs performed after mantle field irradiation were compared to those of 47 salvage SSM-IIBRs following BCT. Both outcomes were compared to the outcome in the contralateral, non-irradiated breast of the subgroup of 23 women in the BCT group.
RESULTS
The groups were comparable in terms of patient- and procedure-related risk factors, except for time lapse after previous therapy, intraoperative device weight, and the fraction of immediate use of a definitive implant. The outcome of SSM-IIBR after mantle field irradiation significantly differs favourably from that after BCT. It matches the outcome observed in non-irradiated breasts.
CONCLUSION
Skin-sparing mastectomy combined with immediate implant-based breast reconstruction is a fully justifiable option for women who previously underwent mantle field irradiation for Hodgkin lymphoma. We feel that the unfavourable outcome observed in women who previously underwent BCT necessitates an alternative reconstructive modality.
Topics: Breast Neoplasms; Female; Hodgkin Disease; Humans; Mammaplasty; Mastectomy; Neoplasm Recurrence, Local; Retrospective Studies
PubMed: 34483080
DOI: 10.1016/j.bjps.2021.08.003 -
Journal of Medical Imaging and... Oct 2015Retrospective analysis was performed at a single institution to assess the responsiveness of mantle cell lymphoma (MCL) to involved-field radiotherapy (IFRT).
INTRODUCTION
Retrospective analysis was performed at a single institution to assess the responsiveness of mantle cell lymphoma (MCL) to involved-field radiotherapy (IFRT).
METHODS
All patients treated with IFRT to at least one site of MCL between 1998 and 2012 were included. There were 25 patients who received radiotherapy to 60 disease sites. Primary endpoint was overall response rate (ORR) infield for the first site of MCL treated per patient. Predictors of ORR were analysed for the primary endpoint. Time to local progression (TLP) infield and progression-free survival were calculated from the start of the first treatment course. Analysis of all sites collectively was also undertaken. Survival analysis was conducted by the Kaplan-Meier method.
RESULTS
ORR rate was 84% for the first site treated per patient. Complete response and partial response rates were 68% and 16% respectively. Median TLP following radiotherapy to the first site was not reached. Infield control rate was 91% at 12 months (95% confidence interval 69-97%). When analysis was performed on all 60 sites, ORR was 85%. Symptomatic improvement occurred after IFRT to 93% of all sites. Systemic progression outside the radiotherapy field was the predominant form of failure following IFRT.
CONCLUSION
Radiotherapy generally induced a clinical response at all levels of dose administered, ranging from 3 to 36 Gy. However, increased durability of local control was suggested with higher doses. Radiotherapy is an effective treatment for palliation of MCL with objective and symptomatic responses seen over a range of radiotherapy doses.
Topics: Aged; Aged, 80 and over; Disease-Free Survival; Dose-Response Relationship, Radiation; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; New South Wales; Prognosis; Radiotherapy Dosage; Radiotherapy, Conformal; Retrospective Studies; Risk Assessment; Risk Factors; Survival Rate; Treatment Outcome
PubMed: 26112608
DOI: 10.1111/1754-9485.12335 -
Internal Medicine Journal Sep 2021
Topics: Hodgkin Disease; Humans
PubMed: 34541768
DOI: 10.1111/imj.15477 -
Science Advances Dec 2023Knowledge of high-pressure melting curves of silicate minerals is critical for modeling the thermal-chemical evolution of rocky planets. However, the melting temperature...
Knowledge of high-pressure melting curves of silicate minerals is critical for modeling the thermal-chemical evolution of rocky planets. However, the melting temperature of davemaoite, the third most abundant mineral in Earth's lower mantle, is still controversial. Here, we investigate the melting curves of two minerals, MgSiO bridgmanite and CaSiO davemaoite, under their stability field in the mantle by performing first-principles molecular dynamics simulations based on the density functional theory. The melting curve of bridgmanite is in excellent agreement with previous studies, confirming a general consensus on its melting temperature. However, we predict a much higher melting curve of davemaoite than almost all previous estimates. Melting temperature of davemaoite at the pressure of core-mantle boundary (~136 gigapascals) is about 7700(150) K, which is approximately 2000 K higher than that of bridgmanite. The ultrarefractory nature of davemaoite is critical to reconsider many models in the deep planetary interior, for instance, solidification of early magma ocean and geodynamical behavior of mantle rocks.
PubMed: 38055828
DOI: 10.1126/sciadv.adj2660 -
Scientific Reports Feb 2021Previous investigation of seismic anisotropy indicates the presence of a simple mantle flow regime beneath the Turkish-Anatolian Plateau and Arabian Plate. Numerical...
Previous investigation of seismic anisotropy indicates the presence of a simple mantle flow regime beneath the Turkish-Anatolian Plateau and Arabian Plate. Numerical modeling suggests that this simple flow is a component of a large-scale global mantle flow associated with the African superplume, which plays a key role in the geodynamic framework of the Arabia-Eurasia continental collision zone. However, the extent and impact of the flow pattern farther east beneath the Iranian Plateau and Zagros remains unclear. While the relatively smoothly varying lithospheric thickness beneath the Anatolian Plateau and Arabian Plate allows progress of the simple mantle flow, the variable lithospheric thickness across the Iranian Plateau is expected to impose additional boundary conditions on the mantle flow field. In this study, for the first time, we use an unprecedented data set of seismic waveforms from a network of 245 seismic stations to examine the mantle flow pattern and lithospheric deformation over the entire region of the Iranian Plateau and Zagros by investigation of seismic anisotropy. We also examine the correlation between the pattern of seismic anisotropy, plate motion using GPS velocities and surface strain fields. Our study reveals a complex pattern of seismic anisotropy that implies a similarly complex mantle flow field. The pattern of seismic anisotropy suggests that the regional simple mantle flow beneath the Arabian Platform and eastern Turkey deflects as a circular flow around the thick Zagros lithosphere. This circular flow merges into a toroidal component beneath the NW Zagros that is likely an indicator of a lateral discontinuity in the lithosphere. Our examination also suggests that the main lithospheric deformation in the Zagros occurs as an axial shortening across the belt, whereas in the eastern Alborz and Kopeh-Dagh a belt-parallel horizontal lithospheric deformation plays a major role.
PubMed: 33531534
DOI: 10.1038/s41598-021-81541-9 -
Science (New York, N.Y.) Feb 2002Although motions at the surface of tectonic plates are well determined, the accompanying horizontal mantle flow is not. We have combined observations of surface...
Although motions at the surface of tectonic plates are well determined, the accompanying horizontal mantle flow is not. We have combined observations of surface deformation and upper mantle seismic anisotropy to estimate this flow field for western North America. We find that the mantle velocity is 5.5 +/- 1.5 centimeters per year due east in a hot spot reference frame, nearly opposite to the direction of North American plate motion (west-southwest). The flow is only weakly coupled to the motion of the surface plate, producing a small drag force. This flow field is probably due to heterogeneity in mantle density associated with the former Farallon oceanic plate beneath North America.
PubMed: 11834831
DOI: 10.1126/science.1066878