Actors on the Scene: Immune Cells in the Myeloma Niche

Two mechanisms are involved in the immune escape of cancer cells: the immunoediting of tumor cells and the suppression of the immune system. Both processes have been revealed in multiple myeloma (MM). Complex interactions between tumor plasma cells and the bone marrow (BM) microenvironment contribute to generate an immunosuppressive milieu characterized by high concentration of immunosuppressive factors, loss of effective antigen presentation, effector cell dysfunction, and expansion of immunosuppressive cell populations, such as myeloid-derived suppressor cells, regulatory T cells and T cells expressing checkpoint molecules such as programmed cell death 1. Considering the great immunosuppressive impact of BM myeloma microenvironment, many strategies to overcome it and restore myeloma immunosurveillance have been elaborated. The most successful ones are combined approaches such as checkpoint inhibitors in combination with immunomodulatory drugs, anti-monoclonal antibodies, and proteasome inhibitors as well as chimeric antigen receptor (CAR) T cell therapy. How best to combine anti-MM therapies and what is the optimal timing to treat the patient are important questions to be addressed in future trials. Moreover, intratumor MM heterogeneity suggests the crucial importance of tailored therapies to identify patients who might benefit the most from immunotherapy, reaching deeper and more durable responses

Imaging Evaluation of Pulmonary and Non-Ischaemic Cardiovascular Manifestations of COVID-19

Coronavirus Disease 2019 (COVID-19) has been a pandemic challenge for the last year. Cardiovascular disease is the most described comorbidity in COVID-19 patients, and it is related to the disease severity and progression. COVID-19 induces direct damage on cardiovascular system, leading to arrhythmias and myocarditis, and indirect damage due to endothelial dysfunction and systemic inflammation with a high inflammatory burden. Indirect damage leads to myocarditis, coagulation abnormalities and venous thromboembolism, Takotsubo cardiomyopathy, Kawasaki-like disease and multisystem inflammatory syndrome in children. Imaging can support the management, assessment and prognostic evaluation of these patients. Ultrasound is the most reliable and easy to use in emergency setting and in the ICU as a first approach. The focused approach is useful in management of these patients due its ability to obtain quick and focused results. This tool is useful to evaluate cardiovascular disease and its interplay with lungs. However, a detailed echocardiography evaluation is necessary in a complete assessment of cardiovascular involvement. Computerized tomography is highly sensitive, but it might not always be available. Cardiovascular magnetic resonance and nuclear imaging may be helpful to evaluate COVID-19-related myocardial injury, but further studies are needed. This review deals with different modalities of imaging evaluation in the management of cardiovascular non-ischaemic manifestations of COVID-19, comparing their use in emergency and in intensive care. View Full-Tex

Short-Term Variations in Neutrophil-to-Lymphocyte and Urea-to-Creatinine Ratios Anticipate Intensive Care Unit Admission of COVID-19 Patients in the Emergency Department

Background: Timely assessment of COVID-19 severity is crucial for the rapid provision of appropriate treatments. Definitive criteria for the early identification of severe COVID-19 cases that require intensive care unit admission are lacking. Methods: This was a single-center, retrospective case-control study of 95 consecutive adults admitted to the intensive care unit (cases) or a medical ward (controls) for laboratory-confirmed COVID-19. Clinical data were collected and changes in laboratory test results were calculated between presentation at the emergency department and admission. Univariate and multivariable logistic regression was performed to calculate odds ratios for intensive care unit admission according to changes in laboratory variables. Results: Of the 95 adults with COVID-19, 25 were admitted to intensive care and 70 to a medical ward after a median 6 h stay in the emergency department. During this interval, neutrophil counts increased in cases and decreased in controls (median, 934 vs. −295 × 106/L; P = 0.006), while lymphocyte counts decreased in cases and increased in controls (median, −184 vs. 109 × 106/L; P < 0.001). In cases, the neutrophil-to-lymphocyte ratio increased 6-fold and the urea-to-creatinine ratio increased 20-fold during the emergency department stay, but these ratios did not change in controls (P < 0.001 for both comparisons). By multivariable logistic regression, short-term increases in the neutrophil-to-lymphocyte ratio (OR = 1.43; 95% CI, 1.16–1.76) and urea-to-creatinine ratio (OR = 1.72; 95% CI, 1.20–2.66) were independent predictors of intensive care unit admission. Conclusion: Short-time changes in neutrophil-to-lymphocyte ratio and urea-to-creatinine ratio emerged as stand-alone parameters able to identify patients with aggressive disease at an early stage

A study of CP violation in B-+/- -> DK +/- and B-+/- -> D pi(+/-) decays with D -> (KSK +/-)-K-0 pi(-/+) final states

A first study of CP violation in the decay modes $B^\pm\to [K^0_{\rm S} K^\pm \pi^\mp]_D h^\pm$ and $B^\pm\to [K^0_{\rm S} K^\mp \pi^\pm]_D h^\pm$, where $h$ labels a $K$ or $\pi$ meson and $D$ labels a $D^0$ or $\overline{D}^0$ meson, is performed. The analysis uses the LHCb data set collected in $pp$ collisions, corresponding to an integrated luminosity of 3 fb$^{-1}$. The analysis is sensitive to the CP-violating CKM phase $\gamma$ through seven observables: one charge asymmetry in each of the four modes and three ratios of the charge-integrated yields. The results are consistent with measurements of $\gamma$ using other decay modes

Study of forward Z + jet production in pp collisions at √s=7 TeV

A measurement of the $Z(\rightarrow\mu^+\mu^-)$+jet production cross-section in $pp$ collisions at a centre-of-mass energy $\sqrt{s} = 7$ TeV is presented. The analysis is based on an integrated luminosity of $1.0\,\text{fb}^{-1}$ recorded by the LHCb experiment. Results are shown with two jet transverse momentum thresholds, 10 and 20 GeV, for both the overall cross-section within the fiducial volume, and for six differential cross-section measurements. The fiducial volume requires that both the jet and the muons from the Z boson decay are produced in the forward direction ($2.0<\eta<4.5$). The results show good agreement with theoretical predictions at the second-order expansion in the coupling of the strong interaction.A measurement of the $Z(\rightarrow\mu^+\mu^-)$+jet production cross-section in $pp$ collisions at a centre-of-mass energy $\sqrt{s} = 7$ TeV is presented. The analysis is based on an integrated luminosity of $1.0\,\text{fb}^{-1}$ recorded by the LHCb experiment. Results are shown with two jet transverse momentum thresholds, 10 and 20 GeV, for both the overall cross-section within the fiducial volume, and for six differential cross-section measurements. The fiducial volume requires that both the jet and the muons from the Z boson decay are produced in the forward direction ($2.0<\eta<4.5$). The results show good agreement with theoretical predictions at the second-order expansion in the coupling of the strong interaction

Measurement of CP asymmetry in B-s(0) -&gt; D-s(-/+) K--/+ decays

We report on measurements of the time-dependent CP violating observables in $B^0_s\rightarrow D^{\mp}_s K^{\pm}$ decays using a dataset corresponding to 1.0 fb$^{-1}$ of pp collisions recorded with the LHCb detector. We find the CP violating observables $C_f=0.53\pm0.25\pm0.04$, $A^{\Delta\Gamma}_f=0.37\pm0.42\pm0.20$, $A^{\Delta\Gamma}_{\bar{f}}=0.20\pm0.41\pm0.20$, $S_f=-1.09\pm0.33\pm0.08$, $S_{\bar{f}}=-0.36\pm0.34\pm0.08$, where the uncertainties are statistical and systematic, respectively. We use these observables to make the first measurement of the CKM angle $\gamma$ in $B^0_s\rightarrow D^{\mp}_s K^{\pm}$ decays, finding $\gamma$ = (115$_{-43}^{+28}$)$^\circ$ modulo 180$^\circ$ at 68% CL, where the error contains both statistical and systematic uncertainties.We report on measurements of the time-dependent CP violating observables in B$_{s}^{0}$  → D$_{s}^{∓}$ K$^{±}$ decays using a dataset corresponding to 1.0 fb$^{−1}$ of pp collisions recorded with the LHCb detector. We find the CP violating observables C$_{f}$ = 0.53±0.25±0.04, A$_{f}^{ΔΓ}$  = 0.37 ± 0.42 ± 0.20, ${A}_{\overline{f}}^{\varDelta \varGamma }=0.20\pm 0.41\pm 0.20$ , S$_{f}$ = −1.09±0.33±0.08, ${S}_{\overline{f}}=-0.36\pm 0.34\pm 0.08$ , where the uncertainties are statistical and systematic, respectively. Using these observables together with a recent measurement of the B$_{s}^{0}$ mixing phase −2β$_{s}$ leads to the first extraction of the CKM angle γ from B$_{s}^{0}$  → D$_{s}^{∓}$ K$^{±}$ decays, finding γ = (115$_{− 43}^{+ 28}$ )° modulo 180° at 68% CL, where the error contains both statistical and systematic uncertainties.We report on measurements of the time-dependent CP violating observables in $B^0_s\rightarrow D^{\mp}_s K^{\pm}$ decays using a dataset corresponding to 1.0 fb$^{-1}$ of pp collisions recorded with the LHCb detector. We find the CP violating observables $C_f=0.53\pm0.25\pm0.04$, $A^{\Delta\Gamma}_f=0.37\pm0.42\pm0.20$, $A^{\Delta\Gamma}_{\bar{f}}=0.20\pm0.41\pm0.20$, $S_f=-1.09\pm0.33\pm0.08$, $S_{\bar{f}}=-0.36\pm0.34\pm0.08$, where the uncertainties are statistical and systematic, respectively. Using these observables together with a recent measurement of the $B^0_s$ mixing phase $-2\beta_s$ leads to the first extraction of the CKM angle $\gamma$ from $B^0_s \rightarrow D^{\mp}_s K^{\pm}$ decays, finding $\gamma$ = (115$_{-43}^{+28}$)$^\circ$ modulo 180$^\circ$ at 68% CL, where the error contains both statistical and systematic uncertainties

Measurement of Upsilon production in collisions at root s=2.76 TeV

The production of $\Upsilon(1S)$, $\Upsilon(2S)$ and $\Upsilon(3S)$ mesons decaying into the dimuon final state is studied with the LHCb detector using a data sample corresponding to an integrated luminosity of 3.3 $pb^{-1}$ collected in proton-proton collisions at a centre-of-mass energy of $\sqrt{s}=2.76$ TeV. The differential production cross-sections times dimuon branching fractions are measured as functions of the $\Upsilon$ transverse momentum and rapidity, over the ranges $p_{\rm T} Upsilon(1S) X) x B(Upsilon(1S) -> mu+mu-) = 1.111 +/- 0.043 +/- 0.044 nb, sigma(pp -> Upsilon(2S) X) x B(Upsilon(2S) -> mu+mu-) = 0.264 +/- 0.023 +/- 0.011 nb, sigma(pp -> Upsilon(3S) X) x B(Upsilon(3S) -> mu+mu-) = 0.159 +/- 0.020 +/- 0.007 nb, where the first uncertainty is statistical and the second systematic

Follow-up of breast cancer: why is it necessary to start a Consensus in 2024?

In Italy, breast cancer is the most frequently diagnosed cancer in women, with 55,900 new cases in 2023 (over 90% in the early stages). Due to the screening, early diagnosis and adjuvant treatment, these patients have a 5-years survival rate of 87% after the diagnosis. There are 834,154 women in Italy with a previous diagnosis of breast cancer: most of these women require a follow-up. The AIOM, ESMO and ASCO Guidelines recommend for early breast cancer (EBC) a clinical follow-up with only physical examination (and eliciting of symptoms) and an annual X-ray mammography, on the basis of the results of two randomized trials published in 1994 that showed no benefit in overall survival with intensive follow-up. However, an Italian survey reported the application by 80% of oncologists of an intensive follow-up based on the individual patient’s risk of recurrence. In fact, the oncologists believe that an early diagnosis of locoregional or distant recurrence may allow an early start of very effective therapies. In this lack of up-to-date scientific data, many questions about follow-up remain unanswered and the few ongoing studies will provide results in several years. Non-compliance with guideline recommendations leads to increased costs for the healthcare system. Furthermore, management varies widely from centre to centre with regard to guideline recommendations, resulting in inequalities between patients. For these reasons, the follow-up of breast cancer should be reconsidered. In the absence of recent scientific evidence, a multidisciplinary group of breast cancer experts has initiated a Consensus on the follow-up of EBC according to the mini-Delphi methodology. The project will be completed by the end of 2024

STAT1 overexpression triggers aplastic anemia: a pilot study unravelling novel pathogenetic insights in bone marrow failure

We identified STAT1 gain of function (GOF) in a 32-year-old female with pallor, weakness, cough, and dyspnea admitted to our Division of Medicine. She had severe oral ulcers (OU), type 1 diabetes (T1DM), and pancytopenia. Bone marrow (BM) biopsy showed the absence of erythroid precursors. Peripheral blood parameters such as neutrophils &lt; 500/mL, reticulocytes &lt; 2%, and BM hypo-cellularity allowed to diagnose severe aplastic anemia. A heterozygous variant (p.520T&gt;C, p.Cys174Arg) of STAT1 was uncovered. Thus, p.Cys174Arg mutation was investigated as potentially responsible for the patient's inborn immunity error and aplastic anemia. Although STAT1 GOF is rare, aplastic anemia is a more common condition; therefore, we explored STAT1 functional role in the pathobiology of BM failure. Interestingly, in a cohort of six patients with idiopathic aplastic anemia, enhanced phospho-STAT1 levels were observed on BM immunostaining. Next, the most remarkable features associated with STAT1 signaling dysregulation were examined: in both pure red cell aplasia and aplastic anemia, CD8+ T cell genetic variants and mutations display enhanced signaling activities related to the JAK-STAT pathway. Inborn errors of immunity may represent a paradigmatic condition to unravel crucial pathobiological mechanisms shared by common pathological conditions. Findings from our case-based approach and the phenotype correspondence to idiopathic aplastic anemia cases prompt further statistically powered prospective studies aiming to elucidate the exact role and theragnostic window for JAK/STAT targeting in this clinical context. Nonetheless, we demonstrate how a comprehensive study of patients with primary immunodeficiencies can lead to pathophysiologic insights and potential therapeutic approaches within a broader spectrum of aplastic anemia cases