Based on the clinical features of myeloma and related malignancies of plasma cells, it has been possible to generate a model system of myeloma progression from a normal plasma cell through ...smouldering myeloma to myeloma and then plasma cell leukaemia. Using this model system we can study at which points the genetic alterations identified through whole-tumour molecular analyses function in the initiation and progression of myeloma. Further genetic complexity, such as intraclonal heterogeneity, and insights into the molecular evolution and intraclonal dynamics in this model system are crucial to our understandings of tumour progression, treatment resistance and the use of currently available and future treatments.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This outcome analysis presents 88 consecutive shoulders presenting with irreparable rotator cuff tears that we treated with arthroscopic superior capsular reconstruction (SCR) using an acellular ...dermal allograft. We also present the concept of superior capsular distance to quantitatively measure the decreased distance present upon restoration of superior capsular integrity.
A retrospective review was conducted of patients treated with arthroscopic SCR with a minimum 12-month follow-up. Outcome analysis was performed via an internet-based outcome-tracking system to evaluate visual analog scale (VAS) and American Shoulder and Elbow Surgeons (ASES) scores. Radiographic analysis of anteroposterior radiographs analyzed acromiohumeral interval and superior capsular distance. Digital dynamometric strength and functional range of motion assessments were also obtained. The main inclusion criteria for patients in this analysis was all patients who underwent superior capsular reconstruction during the time period of this report.
Eighty-six patients with an average age of 59.4 years presented with massive rotator cuff tears (Cofield >5 cm). Outcome data revealed improvement in VAS (4.0-1.5), and ASES (52-82) scores at 1 year (P = .005). Radiographic analysis showed increase in acromiohumeral interval (mean 7.1 mm preoperatively to mean 9.7 mm at 1 year) (P = .049) and superior capsular distance (mean 52.9 mm preoperatively to mean 46.2 mm at 1 year) (P = .011). Strength improved significantly (forward flexion/abduction/external rotation of 4.8/4.1/7.7 lb preoperatively to 9.8/9.2/12.3 lb at 1 year) as well as range of motion (forward flexion/abduction of 120°/103° preoperatively to 160°/159° at 1 year) (P = .044/P = .007/P = .02). At follow-up, 90% of patients were satisfied.
This analysis reveals that arthroscopic SCR with acellular dermal allograft has been successful in decreasing pain and improving function in this patient subset. Radiographic analysis has also shown a consistent and lasting decrease in superior capsular distance and increase in acromiohumeral interval, indicating maintenance of superior capsular stability.
Level IV, retrospective case series.
Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets ...and identify pathways important in disease pathobiology. Using integrated genomics of 1273 newly diagnosed patients with MM, we identified 63 driver genes, some of which are novel, including IDH1, IDH2, HUWE1, KLHL6, and PTPN11. Oncogene mutations are significantly more clonal than tumor suppressor mutations, indicating they may exert a bigger selective pressure. Patients with more driver gene abnormalities are associated with worse outcomes, as are identified mechanisms of genomic instability. Oncogenic dependencies were identified between mutations in driver genes, common regions of copy number change, and primary translocation and hyperdiploidy events. These dependencies included associations with t(4;14) and mutations in FGFR3, DIS3, and PRKD2; t(11;14) with mutations in CCND1 and IRF4; t(14;16) with mutations in MAF, BRAF, DIS3, and ATM; and hyperdiploidy with gain 11q, mutations in FAM46C, and MYC rearrangements. These associations indicate that the genomic landscape of myeloma is predetermined by the primary events upon which further dependencies are built, giving rise to a nonrandom accumulation of genetic hits. Understanding these dependencies may elucidate potential evolutionary patterns and lead to better treatment regimens.
•Using the largest set of patients with newly diagnosed myeloma, we identified 63 mutated driver genes.•We identified oncogenic dependencies, particularly relating to primary translocations, indicating a nonrandom accumulation of genetic hits.
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Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression ...features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R
= 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R
of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.
To elucidate the mechanisms underlying relapse from chemotherapy in multiple myeloma, we performed a longitudinal study of 33 patients entered into Total Therapy protocols investigating them using ...gene expression profiling, high-resolution copy number arrays, and whole-exome sequencing. The study illustrates the mechanistic importance of acquired mutations in known myeloma driver genes and the critical nature of biallelic inactivation events affecting tumor suppressor genes, especially TP53, the end result being resistance to apoptosis and increased proliferation rates, which drive relapse by Darwinian-type clonal evolution. The number of copy number aberration changes and biallelic inactivation of tumor suppressor genes was increased in GEP70 high risk, consistent with genomic instability being a key feature of high risk. In conclusion, the study highlights the impact of acquired genetic events, which enhance the evolutionary fitness level of myeloma-propagating cells to survive multiagent chemotherapy and to result in relapse.
•Hits in driver genes and bi-allelic events affecting tumor suppressors increase apoptosis resistance and proliferation rate–driving relapse.•Excessive biallelic inactivation of tumor suppressors in high-risk cases highlights the need for TP53-independent therapeutic approaches.
Multiple myeloma is a malignancy of terminally differentiated plasma cells in the bone marrow. These plasma cells produce high levels of immunoglobulin which cause end-organ damage. Rearrangements ...within the immunoglobulin loci are a physiological part of B cell development, but these DNA level double-strand breaks may result in interchromosomal translocations. There are five main translocations involving the Ig loci: t(4;14) 12%, t(6;14) 1%, t(11;14) 15%, t(14;16) 3%, and t(14;20) 2%. These are primary events, found in all cells within the tumor clone and are associated with different prognosis. The t(4;14), t(14;16), and t(14;20) are associated with a poor prognosis, whereas the others are associated with a more favorable prognosis. Rearrangements at the MYC locus are also associated with a poor prognosis and increased expression of MYC. MYC rearrangements are frequent (25%) and involve interchromosomal translocations involving Ig loci or other partners, but also include intrachromosomal inversions, duplications and deletions. As such, the Ig and MYC loci are key players in the myeloma genome and including these in any genomic studies is key to understanding the relationship with other abnormalities. We have designed a custom capture of the Ig and MYC loci which can be added to exome or targeted captures to inform on these key events. This saves on performing additional tests to determine these events, which are generally mandatory for any genetic investigations in myeloma. This custom capture is also relevant to other B cell malignancies where MYC and Ig translocations occur.
18F-Fluorodeoxyglucose (FDG)–positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging with background signal suppression (DWIBS) are 2 powerful functional imaging ...modalities in the evaluation of malignant plasma cell (PC) disease multiple myeloma (MM). Preliminary observations have suggested that MM patients with extensive disease according to DWIBS may be reported as being disease-free on FDG-PET (“PET false-negative”). The aim of this study was to describe the proportion of PET false-negativity in a representative set of 227 newly diagnosed MM patients with simultaneous assessment of FDG-PET and DWIBS, and to identify tumor-intrinsic features associated with this pattern. We found the incidence of PET false-negativity to be 11%. Neither tumor load–associated parameters, such as degree of bone marrow PC infiltration, nor the PC proliferation rate were associated with this subset. However, the gene coding for hexokinase-2, which catalyzes the first step of glycolysis, was significantly lower expressed in PET false-negative cases (5.3-fold change, P < .001) which provides a mechanistic explanation for this feature. In conclusion, we demonstrate a relevant number of patients with FDG-PET false-negative MM and a strong association between hexokinase-2 expression and this negativity: a finding which may also be relevant for clinical imaging of other hematological cancers.
•PET false-negativity was seen in 11% of MM patients.•PET false-negativity was associated with low hexokinase-2 expression.
Spatial intratumor heterogeneity is frequently seen in multiple myeloma (MM) and poses a significant challenge for risk classifiers, which rely on tumor samples from the iliac crest. Because ...biopsy-based assessment of multiple skeletal sites is difficult, alternative strategies for risk stratification are required. Recently, the size of focal lesions (FLs) was shown to be a surrogate marker for spatial heterogeneity, suggesting that data from medical imaging could be used to improve risk stratification approaches. Here, we investigated the prognostic value of FL size in 404 transplant-eligible, newly diagnosed MM patients. Using diffusion-weighted magnetic resonance imaging with background suppression, we identified the presence of multiple large FLs as a strong prognostic factor. Patients with at least 3 large FLs with a product of the perpendicular diameters >5 cm2 were associated with poor progression-free survival (PFS) and overall survival (OS; median, 2.3 and 3.6 years, respectively). This pattern, seen in 13.8% of patients, was independent of the Revised International Staging System (RISS), gene expression profiling (GEP)–based risk score, gain(1q), or extramedullary disease (hazard ratio, 2.7 and 2.2 for PFS and OS in multivariate analysis, respectively). The number of FLs lost its negative impact on outcome after adjusting for FL size. In conclusion, the presence of at least 3 large FL is a feature of high risk, which can be used to refine the diagnosis of this type of disease behavior and as an entry criterion for risk-stratified trials.
•The presence of ≥3 large focal lesions is associated with poor outcome in newly diagnosed myeloma patients.•The prognostic impact of multiple large focal lesions is independent of R-ISS, GEP70, and extramedullary disease.
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Abstract
Deciphering Multiple Myeloma evolution in the whole bone marrow is key to inform curative strategies. Here, we perform spatial-longitudinal whole-exome sequencing, including 140 samples ...collected from 24 Multiple Myeloma patients during up to 14 years. Applying imaging-guided sampling we observe three evolutionary patterns, including relapse driven by a single-cell expansion, competing/co-existing sub-clones, and unique sub-clones at distinct locations. While we do not find the unique relapse sub-clone in the baseline focal lesion(s), we show a close phylogenetic relationship between baseline focal lesions and relapse disease, highlighting focal lesions as hotspots of tumor evolution. In patients with ≥3 focal lesions on positron-emission-tomography at diagnosis, relapse is driven by multiple distinct sub-clones, whereas in other patients, a single-cell expansion is typically seen (
p
< 0.01). Notably, we observe resistant sub-clones that can be hidden over years, suggesting that a prerequisite for curative therapies would be to overcome not only tumor heterogeneity but also dormancy.
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