Tixagevimab/Cilgavimab as pre-exposure prophylaxis against SARS-CoV-2 in patients with hematological malignancies.

The approved combination of Tixagevimab/Cilgavimab has been shown to decrease the rate of symptomatic SARS-CoV-2 infection in patients at increased risk of inadequate response to vaccination. However, Tixagevimab/Cilgavimab was tested in a few studies that included patients with hematological malignancies, even if this population has shown an increased risk of unfavorable outcomes following infection (with high rates of hospitalization, intensive care unit admission, and mortality) and poor significant immunization following vaccines. We performed a real-life prospective cohort study to evaluate the rate of SARS-CoV-2 infection following pre-exposure prophylaxis with Tixagevimab/Cilgavimab in anti-spike seronegative patients compared to a cohort of seropositive patients who were observed or received a fourth vaccine dose. We recruited 103 patients with a mean age of 67 years: 35 (34%) received Tixagevimab/Cilgavimab and were followed from March 17, 2022, until November 15, 2022. After a median follow-up of 4.24 months, the 3-month cumulative incidence of infection was 20% versus 12% in the Tixagevimab/Cilgavimab and observation/vaccine groups respectively (HR 1.57; 95% CI: 0.65-3.56; p = 0.34). In this study, we report our experience with Tixagevimab/Cilgavimab and a tailored approach to SARS-CoV-2 infection prevention in patients with hematological malignancies during the SARS-CoV-2 omicron surge.

Light-chain cardiac amyloidosis for the non-expert: pearls and pitfalls.

Cardiac amyloidosis (CA) is an uncommon, progressive, and fatal disease; the two main forms that can affect the heart are transthyretin CA and light chain CA (AL-CA). AL-CA is a medical urgency for which a diagnostic delay can be catastrophic for patients' outcome. In this manuscript, we focus on the pearls and pitfalls that are relevant to achieve a correct diagnosis and to avoid diagnostic and therapeutical delays. Through the aid of three unfortunate clinical cases, some fundamental diagnostic aspects are addressed, including the following: first, a negative bone scintigraphy does not exclude CA, with patients with AL-CA frequently showing no or mild cardiac uptake, and its execution should not delay hematological tests; second, fat pad biopsy does not have a 100% sensitivity for AL amyloidosis and, if negative, further investigations should be performed, particularly if the pre-test probability is high. Third, Congo Red staining is not sufficient to reach a definitive diagnosis and amyloid fibrils typing with mass spectrometry, immunohistochemistry, or immunoelectron microscopy is crucial. To achieve a timely and correct diagnosis, all the necessary investigations must be performed, always considering the yield and diagnostic accuracy of each examination.

CK1α/RUNX2 Axis in the Bone Marrow Microenvironment: A Novel Therapeutic Target in Multiple Myeloma.

Multiple myeloma (MM) is a malignant plasma cell (PC) neoplasm, which also displays pathological bone involvement. Clonal expansion of MM cells in the bone marrow causes a perturbation of bone homeostasis that culminates in MM-associated bone disease (MMABD). We previously demonstrated that the S/T kinase CK1α sustains MM cell survival through the activation of AKT and ß-catenin signaling. CK1α is a negative regulator of the Wnt/ß-catenin cascade, the activation of which promotes osteogenesis by directly stimulating the expression of RUNX2, the master gene regulator of osteoblastogenesis. In this study, we investigated the role of CK1α in the osteoblastogenic potential of mesenchymal stromal cells (MSCs) and its involvement in MM-MSC cross-talk. We found that CK1α silencing in in vitro co-cultures of MMs and MSCs modulated RUNX2 expression differently in PCs and in MSCs, mainly through the regulation of Wnt/ß-catenin signaling. Our findings suggest that the CK1α/RUNX2 axis could be a potential therapeutic target for constraining malignant PC expansion and supporting the osteoblastic transcriptional program of MSCs, with potential for ameliorating MMABD. Moreover, considering that Lenalidomide treatment leads to MM cell death through Ikaros, Aiolos and CK1α proteasomal degradation, we examined its effects on the osteoblastogenic potential of MSC compartments.

Whole-body low-dose CT recognizes two distinct patterns of lytic lesions in multiple myeloma patients with different disease metabolism at PET/MRI.

We evaluated differences in density and 18F-FDG PET/MRI features of lytic bone lesions (LBLs) identified by whole-body low-dose CT (WB-LDCT) in patients affected by newly diagnosed multiple myeloma (MM). In 18 MM patients, 135 unequivocal LBLs identified by WB-LDCT were characterized for inner density (negative or positive Hounsfield unit (HU)), where negative density (HU < 0) characterizes normal yellow marrow whereas positive HU correlates with tissue-like infiltrative pattern. The same LBLs were analyzed by 18F-FDG PET/DWI-MRI, registering DWI signal with ADC and SUV max values. According to HU, 35 lesions had a negative density (- 56.94 ± 31.87 HU) while 100 lesions presented positive density (44.87 ± 23.89 HU). In seven patients, only positive HU LBLs were demonstrated whereas in eight patients, both positive and negative HU LBLs were detected. Intriguingly, in three patients (16%), only negative HU LBLs were shown. At 18F-FDG PET/DWI-MRI analysis, negative HU LBLs presented low ADC values (360.69 ± 154.38 × 10-6 mm2/s) and low SUV max values (1.69 ± 0.56), consistent with fatty marrow, whereas positive HU LBLs showed an infiltrative pattern, characterized by higher ADC (mean 868.46 ± 207.67 × 10-6 mm2/s) and SUV max (mean 5.04 ± 1.94) values. Surprisingly, histology of negative HU LBLs documented infiltration by neoplastic plasma cells scattered among adipocytes. In conclusion, two different patterns of LBLs were detected by WB-LDCT in MM patients. Both types of lesions were indicative for active disease, although only positive HU LBL were captured by 18F-FDG PET/DWI-MRI imaging, indicating that WB-LDCT adds specific information.

Extensive Remineralization of Large Pelvic Lytic Lesions Following Total Therapy Treatment in Patients With Multiple Myeloma.

Osteolytic bone lesions are a hallmark of multiple myeloma (MM) bone disease. Bone destruction is associated with severely imbalanced bone remodeling, secondary to increased osteoclastogenesis and significant osteoblast suppression. Lytic lesions of the pelvis are relatively common in MM patients and are known to contribute to the increased morbidity because of the high risk of fracture, which frequently demands extensive surgical intervention. After observing unexpected radiological improvement in serial large pelvic CT assessment in a patient treated in a total therapy protocol, the radiographic changes of pelvic osteolytic lesions by PET/CT scanning in patients who received Total Therapy 4 (TT4) treatment for myeloma were retrospectively analyzed. Sixty-two (62) patients with lytic pelvic lesions >1 cm in diameter were identified at baseline PET/CT scanning. Follow-up CT studies showed that 27 of 62 patients (43%) with large baseline pelvic lesions achieved significant reaccumulation of radiodense mineralization at the lytic cortical site. The average size of lytic lesions in which remineralization occurred was 4 cm (range, 1.3 to 10 cm). This study clearly demonstrates that mineral deposition in large pelvic lesions occurs in a significant proportion of MM patients treated with TT4, potentially affecting patient outcomes, quality of life, and future treatment strategies. © 2017 American Society for Bone and Mineral Research.

Search for an Ultralight Scalar Dark Matter Candidate with the AURIGA Detector.

A search for a new scalar field, called moduli, has been performed using the cryogenic resonant-mass AURIGA detector. Predicted by string theory, moduli may provide a significant contribution to the dark matter (DM) component of our Universe. If this is the case, the interaction of ordinary matter with the local DM moduli, forming the Galaxy halo, will cause an oscillation of solid bodies with a frequency corresponding to the mass of moduli. In the sensitive band of AURIGA, some 100 Hz at around 1 kHz, the expected signal, with Q=△f/f∼10^{6}, is a narrow peak, △f∼1 mHz. Here the detector strain sensitivity is h_{s}∼2×10^{-21} Hz^{-1/2}, within a factor of 2. These numbers translate to upper limits at 95% C.L. on the moduli coupling to ordinary matter (d_{e}+d_{m_{e}})≲10^{-5} around masses m_{ϕ}=3.6×10^{-12} eV, for the standard DM halo model with ρ_{DM}=0.3 GeV/cm^{3}.

Spontaneous splenic rupture following stem cell mobilization with G-CSF and plerixafor in AL amyloidosis.

BACKGROUND: AL amyloidosis is a rare plasma cell dyscrasia with multiorgan involvement. Good risk patients are candidate to high dose chemotherapy and autologous stem cell transplantation. However both transplantation and stem cell collection entail significant risk in such patients. Plerixafor is a novel mobilizing agent approved for use in "poor mobilizer" patients with lymphoma and multiple myeloma; experience in systemic amyloidosis patients is limited. CASE REPORT: We describe a case of spontaneous splenic rupture following administration of G-CSF and plerixafor in a patient with AL amyloidosis who previously underwent heart transplantation due to amyloid heart involvement. RESULTS AND CONCLUSION: This is the first report of spontaneous splenic rupture following stem cell mobilization with G-CSF and plerixafor in AL amyloidosis. The role of plerixafor has to be established. AL amyloidosis patients undergoing stem cell mobilization need careful monitoring of signs and symptoms of spontaneous splenic rupture.

Cytogenetic Impact on Lenalidomide Treatment in Relapsed/Refractory Multiple Myeloma: A Real-Life Evaluation.

INTRODUCTION: In this retrospective real-life study in relapsed/refractory multiple myeloma patients, we analyzed clinical and biologic features distinguishing patients with rapidly progressing disease while receiving lenalidomide therapy from those without progression. PATIENTS AND METHODS: According to time of stopping lenalidomide, patients were subdivided into 3 groups: early stop (ES) (n = 23), when therapy was discontinued within 6 months; intermediate (INT) (n = 23), when therapy was stopped between 7 to 24 months; and long survival (LS) (n = 45), when therapy was maintained for more than 2 years. The median age of the whole cohort was 70 years (range, 42-85 years); 40% had an International Staging System score of 2 or 3. RESULTS: High-risk cytogenetic findings, including 1q gain, was reported in 65% ES, 43% INT, and 21% LS. Overall response rate was 63%, with median progression-free survival and overall survival of 33 and 56 months, respectively. CONCLUSION: Although high-risk cytogenetic findings negatively affect progression-free survival and overall survival, 28% of cytogenetic high-risk patients experienced long survival, provided that lenalidomide therapy was not discontinued, thus pointing to the role of maintenance therapy in this subset of patients.

EUTOS score predicts long-term outcome but not optimal response to imatinib in patients with chronic myeloid leukaemia.

To test the recently developed EUTOS score in predicting optimal response to imatinib and the long-term outcome, 265 patients with early chronic phase chronic myeloid leukaemia treated with standard dose imatinib were analysed. Achievement of optimal response endpoints were higher in low-risk patients, though the difference was not statistically significant: PCyR at 6th month 86% vs 67% (p=0.06), CCyR at 12th month 80% vs 63% (p=0.09), MMR at 18th month 61% vs 36% (p=0.11). However, EUTOS score was predictive for the long-term response. With a median follow-up of 61 months, 53% high-risk patients experienced imatinib failure, compared to 23% in the low-risk group (p=0.013). Among high-risk patients, 4/17 (23%) progressed to accelerated/blastic phase or died, compared to 11/248 (5%) low-risk patients, with 5-year progression-free survival rates of 84±10% and 96±1%, respectively (p=0.04). Our data confirm that EUTOS score envisions the long-term outcome of imatinib therapy.

Effects of second-generation tyrosine kinase inhibitors towards osteogenic differentiation of human mesenchymal cells of healthy donors.

The BCR-ABL inhibitor imatinib is a standard first-line therapy for patients with chronic myeloid leukemia. However, it has been demonstrated that this long-term treatment is associated with altered bone metabolism. The mechanisms of this effect are not fully understood, but an inhibition of the platelet-derived growth factor receptor (PDGF-R) ß axis has been suspected on the basis of some in vitro findings. We evaluated the osteoblastic differentiation of mesenchymal stem cells derived from bone marrow (hBM-MSCs) after in vitro treatment with dasatinib, nilotinib or bosutinib. Human bone marrow mesenchymal stem cells were induced to differentiate in osteoblastic cells by treatment with osteogenic medium with or without dasatinib, nilotinib or bosutinib. We found that the addition of dasatinib, and to a greater extend nilotinib, induced expression of osteogenic mRNA markers as compared with cultures with standard medium or osteogenic medium only. However, treatment with bosutinib did not induce an increase of osteogenic markers. In conclusion, we show that besides imatinib, other tyrosine kinase inhibitors (TKIs) such as dasatinib and nilotinib, but not bosutinib, increase osteogenic markers in hBM-MSCs. Because bosutinib differs from the other TKIs because of its low affinity to other kinases such as PDGF-R, these experiments suggest that inhibition of PDGF-R may be involved in the induction of osteoblastogenesis by TKIs.