The IMPACT study: early loss of skeletal muscle mass in advanced pancreatic cancer patients

Abstract Background Pancreatic cancer (PC) patients have multiple risk factors for sarcopenia and loss of skeletal muscle mass (LSMM), which may cause greater treatment toxicities, reduced response to cancer therapy, prolonged hospitalization, impaired quality of life, and worse prognosis. Methods This is a retrospective study on advanced PC patients treated at the Department of Oncology of Udine, Italy, from January 2012 to November 2017. Among 162 patients who received chemotherapy, 94 consecutive patients with an available computed tomography (CT) scan were retrospectively analyzed. The primary objective of our study was to explore if an early LSMM ≥ 10% (measured at first radiological evaluation and compared with baseline) and/or baseline sarcopenia may impact prognosis. Baseline sarcopenia was defined according to Prado's criteria. Skeletal muscle area was measured as cross‐sectional areas (cm2) using CT scan data through the Picture archiving and communication system (PACS) image system. Results In the whole cohort, 48% of patients were ≤70 years old, and 50% had metastatic disease. At baseline, 73% of patients had sarcopenia, and 16% presented a visceral fat area ≥ 44 cm2/m2. Overall, 21% experienced an early LSMM ≥ 10%. Approximately 33% of sarcopenic patients at baseline and ~35% of patients with early LSMM ≥ 10% had a body mass index > 25 kg/m2. Of note, 71% of patients were evaluated by a nutritionist, and 56% received a dietary supplementation (oral and/or parenteral). After a median follow‐up of 30.44 months, median overall survival (OS) was 11.28 months, whereas median progression‐free survival (PFS) was 5.72 months. By multivariate analysis, early LSMM ≥ 10% was significantly associated with worse OS [hazard ratio (HR): 2.16; 95% confidence interval (CI) 1.23–3.78; P = 0.007] and PFS (HR: 2.31; 95% CI 1.30–4.09; P = 0.004). Moreover, an exploratory analysis showed that inflammatory indexes, such as neutrophil–lymphocyte ratio variation, impact early LSMM ≥ 10% (odds ratio 1.31, 95% CI 1.06–1.61, P = 0.010). Conclusions Early LSMM ≥ 10% has a negative prognostic role in advanced PC patients. Further prospective investigations are needed to confirm these preliminary data

Epidemiology and clinical course of severe acute respiratory syndrome coronavirus 2 infection in cancer patients in the Veneto Oncology Network: The Rete Oncologica Veneta covID19 study

Introduction: Coronavirus disease 2019 (COVID-19) pandemic started in Italy with clusters identified in Northern Italy. The Veneto Oncology Network (Rete Oncologica Veneta) licenced dedicated guidelines to ensure proper care minimising the risk of infection in patients with cancer. Rete Oncologica Veneta covID19 (ROVID) is a regional registry aimed at describing epidemiology and clinical course of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with cancer. Materials and methods: Patients with cancer diagnosis and documented SARS-CoV-2 infection are eligible. Data on cancer diagnosis, comorbidities, anticancer treatments, as well as details on SARS-CoV-2 infection (hospitalisation, treatments, fate of the infection), have been recorded. Logistic regression analysis was applied to calculate the association between clinical/laboratory variables and death from any cause. Results: One hundred seventy patients have been enrolled. The median age at time of the SARS-CoV infection was 70 years (25-92). The most common cancer type was breast cancer (n = 40). The majority of the patients had stage IV disease. Half of the patients had two or more comorbidities. The majority of the patients (78%) presented with COVID-19 symptoms. More than 77% of the patients were hospitalized and 6% were admitted to intensive care units. Overall, 104 patients have documented resolution of the infection. Fifty-seven patients (33%) have died. In 29 cases (17%), the cause of death was directly correlated to SARS-CoV-2 infection. Factors significantly correlated with the risk of death were the following: Eastern Cooperative Oncology Group performance status (PS), age, presence of two or more comorbidities, presence of dyspnoea, COVID-19 phenotype ≥ 3, hospitalisation, intensive care unit admission, neutrophil/lymphocyte ratio and thrombocytopenia. Conclusions: The mortality rate reported in this confirms the frailty of this population. These data reinforce the need to protect patients with cancer from SARS-CoV-2 infection

Bone health and body composition in transgender adults before gender-affirming hormonal therapy: data from the COMET study

Purpose: Preliminary data suggested that bone mineral density (BMD) in transgender adults before initiating gender-affirming hormone therapy (GAHT) is lower when compared to cisgender controls. In this study, we analyzed bone metabolism in a sample of transgender adults before GAHT, and its possible correlation with biochemical profile, body composition and lifestyle habits (i.e., tobacco smoke and physical activity). Methods: Medical data, smoking habits, phospho-calcic and hormonal blood tests and densitometric parameters were collected in a sample of 125 transgender adults, 78 Assigned Females At Birth (AFAB) and 47 Assigned Males At Birth (AMAB) before GAHT initiation and 146 cisgender controls (57 females and 89 males) matched by sex assigned at birth and age. 55 transgender and 46 cisgender controls also underwent a complete body composition evaluation and assessment of physical activity using the International Physical Activity Questionnaire (IPAQ). Results: 14.3% of transgender and 6.2% of cisgender sample, respectively, had z-score values < -2 (p = 0.04). We observed only lower vitamin D values in transgender sample regarding biochemical/hormonal profile. AFAB transgender people had more total fat mass, while AMAB transgender individuals had reduced total lean mass as compared to cisgender people (53.94 ± 7.74 vs 58.38 ± 6.91, p < 0.05). AFAB transgender adults were more likely to be active smokers and tend to spend more time indoor. Fat Mass Index (FMI) was correlated with lumbar and femur BMD both in transgender individuals, while no correlations were found between lean mass parameters and BMD in AMAB transgender people. Conclusions: Body composition and lifestyle factors could contribute to low BMD in transgender adults before GAHT

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p &lt; .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p &lt; .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come

Exploring biological and functional features of HSCs from different sources for gene therapy of β-thalassemia

Gene therapy for inherited diseases affecting the hematopoietic system requires transplantation and engraftment of a high number of autologous genetically engineered hematopoietic stem cells (HSCs). In the context of gene therapy for nonfatal diseases, as thalassemia, a favorable balance between the extent of conditioning of the host bone marrow (BM) and the adequate dose of transduced HSCs needs to be achieved. For adult thalassemic patients, the issue of HSC source is crucial as the minimal target dose poses a challenge for the use of steady-state BM. Peripheral blood (PB) mobilized CD34+ cells represent a valid alternative, but intrinsic characteristics of thalassemic patients (splenomegaly and thrombophilia) dictate caution in the choice of full dose G-CSF as mobilizing agent. The recently available mobilizing agent Plerixafor, which reversibly inhibits the stromal cell-derived factor1/CXC-motif receptor-4 (SDF-1–CXCR4) interaction within the BM microenvironment could represent an attractive alternative. We characterized HSCs mobilized from adult patients affected by transfusion dependent β-thalassemia by Plerixafor (Thal Plx PB) or by the combination of G-CSF + Plerixafor (Thal G+Plx PB), as collaborative study between Hematology-BMT Unit and TIGET, at San Raffaele Hospital in Milan. In addition, we had the unique opportunity to compare Plerixafor-mobilized PB cells with BM CD34+ cells pre- and post-Plerixafor treatment, derived from the same patient. CD34+ cells purified from patients’ leukoaphereses were analyzed for their biological and functional properties, subpopulations composition and expression profile. In vivo reconstitution potential and lymphomyeloid differentiation were tested following transplantation in NOD/SCID/IL2rγnull (NSG) mice. We performed comparative studies using thalassemic patient-derived samples and also BM and G-CSF-mobilized CD34+ cells from healthy donors, in order to unravel whether different sources might determine intrinsic molecular and functional features of HSCs. We showed that Plerixafor mobilizes high-quality HSCs able to provide stable long-term hematopoietic engraftment in NSG mice. Moreover, the quiescence status of these cells correlates with the enriched scid-repopulating cell frequency, in comparison to the other sources. The insights into the transcriptional program reveal the molecular machinery underlying “stemness” features of cells derived from different sources, defining their specific functional properties. Noteworthy, CD34+ cells exposed to Plerixafor and harvested from the BM acquire an intermediate signature between resident and circulating cells, suggesting an effect of this agent on HSC function. Mobilized CD34+ cells isolated from thalassemic samples were also efficiently transduced with the GLOBE lentiviral vector carrying the β-globin gene, and showed stable transgene expression. The availability of high numbers of Thal Plx PB and Thal G+Plx PB CD34+ cells allowed us to test in vitro different transduction protocols and also to evaluate the reconstitution potential of transduced cells in NSG mice. These experiments allowed to optimize culture conditions and to confirm the maintenance of engraftment and repopulation capacities of the mobilized cells also after in vitro manipulation. Our studies uncovered previously unknown unique HSC properties shaped by their origin and illuminate the choice of different transplantation strategies accordingly to the clinical need. The availability of new sources of HSCs, superior in terms of CD34+ cell yield, transduction efficiency and biological features to BM, indeed, would have a significant impact on the feasibility and efficacy of gene therapy

Targeting the Hematopoietic Stem Cell Niche in β-Thalassemia and Sickle Cell Disease

In the last decade, research on pathophysiology and therapeutic solutions for β-thalassemia (BThal) and sickle cell disease (SCD) has been mostly focused on the primary erythroid defect, thus neglecting the study of hematopoietic stem cells (HSCs) and bone marrow (BM) microenvironment. The quality and engraftment of HSCs depend on the BM microenvironment, influencing the outcome of HSC transplantation (HSCT) both in allogeneic and in autologous gene therapy settings. In BThal and SCD, the consequences of severe anemia alter erythropoiesis and cause chronic stress in different organs, including the BM. Here, we discuss the recent findings that highlighted multiple alterations of the BM niche in BThal and SCD. We point out the importance of improving our understanding of HSC biology, the status of the BM niche, and their functional crosstalk in these disorders towards the novel concept of combined therapies by not only targeting the genetic defect, but also key players of the HSC–niche interaction in order to improve the clinical outcomes of transplantation

Inhibition of FGF23 is a therapeutic strategy to target hematopoietic stem cell niche defects in β-thalassemia

Clinical evidence highlights a relationship between the blood and the bone, but the underlying mechanism linking these two tissues is not fully elucidated. Here, we used beta-thalassemia as a model of congenital anemia with bone and bone marrow (BM) niche defects. We demonstrate that fibroblast growth factor 23 (FGF23) is increased in patients and mice with beta-thalassemia because erythropoietin induces FGF23 overproduction in bone and BM erythroid cells via ERK1/2 and STAT5 pathways. We show that in vivo inhibition of FGF23 signaling by carboxyl-terminal FGF23 peptide is a safe and efficacious therapeutic strategy to rescue bone mineralization and deposition in mice with beta-thalassemia, normalizing the expression of niche factors and restoring hematopoietic stem cell (HSC) function. FGF23 may thus represent a molecular link connecting anemia, bone, and the HSC niche. This study provides a translational approach to targeting bone defects and rescuing HSC niche interactions, with potential clinical relevance for improving HSC transplantation and gene therapy for hematopoietic disorders

Hematopoietic stem cell function in β-thalassemia is impaired and is rescued by targeting the bone marrow niche

Hematopoietic stem cells (HSCs) are regulated by signals from the bone marrow (BM) niche, which tune hematopoiesis at steady state and in hematologic disorders. To understand the HSC-niche interactions in altered non-malignant homeostasis, we elected as a paradigm β-thalassemia, a hemoglobin disorder. In this severe congenital anemia, secondary alterations to the primary hemoglobin defect have a potential impact on HSC-niche crosstalk. Here we report that HSCs in thalassemic mice (th3) have an impaired function, caused by the interaction with an altered BM niche. The HSC self-renewal defect is rescued upon transplantation into a normal microenvironment, thus proving the active role of BM stroma. Consistently with the common finding of osteoporosis in patients, we found reduced bone deposition with decreased levels of parathyroid hormone (PTH), which is a key regulator of bone metabolism but also of HSC activity. In vivo activation of PTH signaling through the reestablished Jagged1 and osteopontin levels correlates with the rescue of the functional pool of th3 HSCs by correcting HSC-niche crosstalk. Reduced HSC quiescence is confirmed in thalassemic patients, along with altered features of the BM stromal niche. Our findings uncover a defect of HSCs in β-thalassemia induced by an altered BM microenvironment and provide new relevant insight for improving transplantation and gene therapy approaches

Study of the biotrophic transportome in the arbuscular mycorrhiza

équipe SPEPôle IPMUBStudy of the biotrophic transportome in the arbuscular mycorrhiza. 110 Congresso SBI Società Botanica Italiana Onlus, II international plant science conference (IPSC