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COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T-cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56dimCD16hi NK cells linked positively to circulating IL-15. CD8+ T cell activation was apparent without signs of exhaustion. While cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery-fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19., A multiparameter metric developed by integrating circulating cytokines, multimodal single cell profiling, cell surface protein and immune cell analyses of COVID-19 patients over time, reveals a late wave of diverging inflammatory and host immune responses that predicts recovery versus fatality.

Introduction The diagnostic accuracy of fluorine-18–fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in staging mantle-cell lymphoma has not yet investigated. The aim of this 2-center retrospective study was to investigate the utility of 18F-FDG PET/CT in assessing nodal, splenic, bone marrow (BM), and gastrointestinal (GI) disease compared to CT, BM, and GI endoscopy; and to assess its clinical impact. Patients and Methods One hundred twenty-two patients with histologically proven mantle-cell lymphoma were included. PET/CT BM findings were considered positive if isolated/multiple focal uptake in the BM not explained by benign findings and/or diffuse BM uptake higher than liver with/without focal uptakes were present. PET/CT findings were considered positive for GI involvement in the presence of isolated/multiple focal uptake in the GI organ. Results All patients had positive PET/CT showing the presence of at least one hypermetabolic lesion, with the exception of one case. PET/CT results, compared to CT, detected more nodal and/or splenic lesions in 26 patients. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET/CT for BM were 52%, 98%, 97%, 65%, and 74%; for GI 64%, 91%, 69%, 90%, and 85%; and for GI excluding diabetic patients, 78%, 92%, 72%, 94%, and 89%. PET/CT permitted upstaging of 21 cases and downstaging of 2. Conclusion 18F-FDG PET/CT showed excellent detection rate in nodal and splenic disease—a rate better than CT. For BM and GI evaluation, in order to reach good accuracy, the selection of patients and the use of specific criteria for evaluation of these organs seems to be crucial. Moreover, PET/CT altered the management and therapeutic approach in about 20% of patients.

Background sustained MRD negativity is emerging as a surrogate biomarker of patients (pts)’ outcome in clinical trials. We implemented this tool in our clinical practice and we analyzed outcome according to sustained MRD negativity in MM pts treated with autologous stem cell transplantation (ASCT) at our Institution. Methods We retrospectively analyzed the outcome of 77 newly diagnosed MM pts (median age 61 years) diagnosed between January 2015 to December 2019 in ≥ VGPR after ASCT. Bone marrow samples were collected for MRD by 8-color FCM (Sn 10-5) at day +100 after ASCT, before maintenance. Sustained 1 year MRD negativity was also evaluated and the prognostic impact of MRD status on PFS and OS was analyzed. Results out of 77 pts, 28 (36%) were ISS stage 3 and 18 (23%) showed high risk cytogenetics. Patients were treated with the following induction regimens: VTD 51, VRD 5, Dara-VRD 5, KRD 14, KCD 2. Single ASCT with MEL200 conditioning was performed in 49 pts (64%), whereas 28 pts (36%) received double ASCT. Subsequent maintenance was performed with lenalidomide (70), daratumumab-lenalidomide (5), carfilzomib-lenalidomide (2). Response rates were VGPR 26%, CR 61% and sCR 13%. MRD before maintenance was positive in 20 pts (26%) and negative in 57 (74%). Sustained MRD negativity lasting ≥ 1 year was documented in 49 pts (64%), whereas early loss of MRD negative status was observed in 8 (10%) of cases. After a median follow up of 40.2 months, PFS was significantly longer in pts with sustained MRD negativity (≥1 year) compared to MRD positive patients before maintenance: median NR vs 41.4 months, p 0.0002, HR 0.17 (0.044-0.65). The worst PFS (24.7 months) was observed in pts with early loss of MRD negativity ( Conclusion we confirm the predictive value of MRD assessment after ASCT and therefore the importance of achieving sustained MRD negativity regardless of different treatment strategies. Moreover, the detection of early loss of MRD negativity can help the physician to identify pts with particularly poor prognosis

Background: Six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) or R-CHOP-like chemotherapy are the standard treatment for aggressive B-cell non-Hodgkin's lymphoma. We hypothesized that four cycles of CHOP plus six applications of rituximab (4x R-CHOP+2xR) are non-inferior to six cycles of R-CHOP in a population with favorable prognosis. Methods: We randomized patients 18 to 60 years of age, stage I-II disease, normal serum lactate dehydrogenase concentration, good ECOG performance status 0-1, without bulky disease (maximal tumor diameter

Background Tumor regression after antiviral therapy (AT) is in favor of an etiological role of hepatitis C virus (HCV) in non-Hodgkin's B-cell lymphomas (NHL). Patients and methods We carried out a cohort study of 704 consecutive HIV-negative, HCV-positive patients with indolent NHL diagnosed and treated from 1993 to 2009 in 39 centers of the Fondazione Italiana Linfomi; 134 patients were managed with AT for lymphoma control. Results For entire cohort, 5-year overall survival (OS) was 78% [95% confidence interval (CI): 74%–82%] and 5-year progression-free survival (PFS) was 48% (95% CI: 44%–53%). In multivariate analysis, the use of AT during the patients’ life had positive impact on OS. Forty-four of the 100 patients treated with first-line AT achieved a complete remission (CR) and 33 a partial response (PR). HCV-RNA clearance was achieved in 80 patients and was related to lymphoma response. At a median follow-up of 3.6 years, 5-year PFS was 63% (95% CI: 50%–73%). CR + PR rate was 85% with AT as second-line treatment. Conclusion AT produces HCV-RNA clearance and consequent tumor regression in most patients with HCV-related indolent NHL. AT used at any time is associated with improved OS. Consequently, AT can be considered an option for patients with indolent lymphomas who do not need immediate cytoreductive treatment.

Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) fingerprinting has recently become an effective instrument for rapid microbiological diagnostics and in particular for identification of micro-organisms directly in a positive blood culture. The aim of the study was to evaluate a collection of 82 stored yeast isolates from bloodstream infection, by MALDI-TOF MS; 21 isolates were identified also directly from positive blood cultures and in the presence of other co-infecting micro-organisms. Of the 82 isolates grown on plates, 64 (76%) were correctly identified by the Vitek II system and 82 (100%) by MALDI-TOF MS; when the two methods gave different results, the isolate was identified by PCR. MALDI-TOF MS was unreliable in identifying two isolates (Candida glabrata and Candida parapsilosis) directly from blood culture; however, direct analysis from positive blood culture samples was fast and effective for the identification of yeast, which is of great importance for early and adequate treatment.

Background Tailoring treatment intensity is critical in Hodgkin's lymphoma (HL). Ongoing prognostic parameters may be an useful adjunct to pretreatment stratification. We used the kinetics of computed tomography (CT) scan response and residual gallium (Ga)-67 uptake to better stratify risk. Materials and methods Patients received 4–8 adriamycin, bleomycin, vinblastine and dacarbazine courses according to stage. Disease was reassessed evaluating late computed tomography scan response improvement (CTRI) and Ga-67 uptake. Patients received no further treatment, radiotherapy (RT) or additional chemotherapy + RT according to the presence of none (low risk), one (intermediate risk) and both parameters (high risk). Patients with bulky mediastinum received RT anyhow. Results Among 102 assessable patients, 35 showed late CTRI and 9 residual Ga-67 uptake. In 30 patients with bulky mediastinum, the 3-year progression-free survival (PFS) was significantly better when neither parameter was present (100% versus 69%; P = 0.02). In 72 patients without bulky mediastinum, treatment was tailored according to risk assignment. Relapses occurred in 5 of 47 low-risk and 3 of 21 intermediate-risk patients, with no differences between the two groups, and in 3 of 4 high-risk patients. Conclusion This study shows that two on-treatment parameters, late CTRI and residual Ga-67 uptake, can predict PFS in HL and identify patients in which RT can be spared without apparently affecting the outcome.

The aims of the study were to evaluate the long-term efficacy and tolerability of different doses of interferon-alpha (IFN alpha) and different durations of treatment in chronic hepatitis C by comparing 3 or 6 mega units (MUs) three times weekly given for either 12 or 24 months, and the possibility of obtaining a response in non-responder patients by increasing the dose or by administering IFN daily. A total of 504 patients with non-cirrhotic chronic hepatitis C enrolled in a multicentre study were consecutively assigned to receive either 3 (255 patients) or 6 MU (249 patients) of lymphoblastoid IFN alpha 3 times a week (tiw). At the 12th month of therapy, patients with normal aminotransferase (AMT) in both groups were either given IFN for an additional 12 months with an unmodified or halved dose, or else discontinued therapy. For patients with unmodified AMT levels after 6 months of therapy, the IFN dose was doubled in the 3-MU group, while it was administered at 3 MU daily in the 6-MU group. When no improvement was achieved, therapy was discontinued; otherwise it was prolonged until the 18th month. Patients were followed up for 12 months after discontinuing IFN. Of the 255 patients enrolled at 3 MU, therapy was stopped during the first 6 months in 36 patients (14.1%) because of side effects, and in 24 (9.4%) because of lack of cooperation. Of the remaining 195 patients at the 6th month of therapy, 119 (61%) had normal and 76 (39%) unmodified AMT levels; 14 of the 76 normalized AMT after doubling the dose of IFN, but only 5 (6.6%) had a sustained response. Of the 119 patients with normal AMT, 40 discontinued IFN at the 12th month (schedule A), 39 remained at 3 MU tiw (schedule B) and 40 were given a dose of 1.5 MU tiw (schedule C) for an additional 12 months. At the end of follow-up, 23/40 (57.5%) patients in schedule A, 31/39 (79.5%) on schedule B and 29/40 (72.5%) on schedule C still had normal AMT (A vs. B p = 0.04). In an intention-to-treat analysis, the sustained response rate for patients enrolled at 3 MUs, including the 5 initial non-responders, was 34.5%. Of the 249 patients enrolled at 6 MU, therapy was discontinued during the first 6 months for 39 (15.7%) because of side effects, and for 27 (10.8%) because of lack of cooperation. Of the remaining 183 patients at the 6th month of therapy, 110 (60%) had normal and 73 (40%) unmodified AMT levels. Of the 73 patients, 55 accepted the daily regimen and 8 of them (14.5%) showed a sustained response. Of the 110 patients with normal AMT, 32 (29.1%), despite normalization of AMT, spontaneously discontinued IFN or reduced the dose because of a poor quality of life, while 78 continued with 6 MU until the 12th month, when therapy was discontinued for 28 (schedule A1); 24 patients were given an unmodified dose (schedule B1) and 26 a halved dose (schedule C1) for an additional 12 months. At the end of follow-up, 18/28 (64.3%) patients on schedule A1, 19/24 (79.2%) on schedule B1 and 19/26 (73.1%) on C1 still had normal AMT (p = NS). In an intention-to-treat evaluation, the sustained response rate for patients enrolled at 6 MU, including the 8 from the daily treatment, was 25.7% (64/249). HCV viraemia was undetectable 1 year after discontinuation of IFN in 72.6% of patients with a sustained response. Sustained response was observed in 36.4% of patients with minimal, 46.6% of those with mild, and 33.3% with moderate or severe histological activity (p = NS). The rate of sustained response was lower in patients with genotype 1b (23.6%) than in those with genotype 2a (67.8%, p = 0.002) or genotype 3 (50%, p = 0.03), irrespective of the histological activity. In conclusion, 6 MU IFN alpha are no more effective than 3 MU in inducing a sustained response in treatments of both 12 and 24 months. A 24-month treatment is more effective than a 12-month treatment in maintaining a biochemical response after discontinuation of IFN. In terms of efficacy, compliance and cost, 3 MU for 24 months app

This paper examines whether the export decision of firms is affected by their ownership structure, specifically it looks at whether family control is an obstacle to entering foreign markets. The underlying assumption is that family firms are risk averse. Risk aversion may be an obstacle to entering foreign markets, as far as these are perceived as more volatile and risky than the domestic one, particularly when such choice entices bearing relatively high sunk costs. We develop an illustrative theoretical model that shows how the combination between high risk aversion and low initial productivity may hinder family firms’ decision to enter foreign markets, particularly distant ones. The empirical analysis, based on a detailed panel data set of Italian firms covering the years from 1995 to 2003, confirms such predictions by showing that family controlled firms do indeed export less than other type of companies even after controlling for firm heterogeneity in productivity, size, technology and access to credit.

A large body of literature in International Economics has analysed the impact of increased import competition on domestic firms. The link between firm-level exports and changes in the competitive environment on foreign markets is less well understood, however. This is despite the fact that exports make up a significant and growing share of total manufacturing production in most countries. We derive a theory-based econometric specification linking destination-specific exports to foreign demand and the degree of competitiveness or “crowdedness” of a foreign market. The latter is a summary measure of the number and productive efficiency of firms competing in a given market and the barriers impeding their access, such as tariffs or physical distance. We estimate this specification on a large sample of Italian manufacturing firms in 1992-2003 and use the results for a series of counterfactual experiments. Our findings indicate that increased numbers and efficiency of foreign firms and improvements in their access to destination markets have reduced Italian exports by around 0.2-0.4% per year. This is similar to the effects of tariff reductions for Italian firms (+0.3%/year) but smaller than the impact of higher unit labour costs (-1.4%/year) and less favourable exchange rates (-2.0%/year). By far the most important determinant of export performance was foreign demand growth, however, raising Italian exports by up to 5.3% per year or almost 60% over the sample period. Our results also indicate that China’s impact on Italian export performance is small and if anything positive. Much more important in explaining the loss of export market shares in recent years has been the relatively slow demand growth in Italy’s main export market, the EU15.

This paper examines the relationship between the exposure to foreign trade and productivity growth for a sample of Indian manufacturing firms. By testing a catching up model of productivity growth, it sheds some light on the nature of the relationship between the exposure to foreign competition and productivity growth. It finds a non linear relationship between firms' export share and productivity gains. Productivity growth declines with the share of exports on total sales, up to a threshold ranging between 40 and 50 per cent and it increases thereafter. This result appears to be dominated by the behaviour of firms in traditional sectors like textile and clothing. In more technology intensive sectors, like pharmaceuticals, productivity gains also arise for smaller export shares. One likely explanation of this finding is that being successful in the export market for exporters of traditional products also requires investments in technological upgrading. These investments are less likely to be viable for marginal exporters. In fact, firms with a larger than 50 percent share of exports are also found to be more capital intensive and to use newer machinery than non exporters or marginal exporters. In contrast we find that human capital is not significantly different for different categories of firms.