Rosaria Sancetta

Positron emission tomography in the staging of patients with Hodgkin's lymphoma. A prospective multicentric study by the Intergruppo Italiano Linfomi.

In this prospective multicentric study, we investigated the contribution of positron emission tomography (PET) scanning to the staging of Hodgkin’s lymphoma (HL) by computed tomography (CT) and attempted to determine whether it has any impact on therapeutic approach. One hundred eighty six consecutive patients with HL from six Italian centers were enrolled in this study. They were staged with conventional methods; 2-[fluorine-18]fluoro-2-deoxy-d-glucose PET scanning were prospectively compared to CT. CT and FDG-PET stages were concordant in 156 patients (84%) and discordant in 30 patients (16%). PET stage in comparison to CT stage was higher in 27 patients (14%) and lower in 3 patients (1%). The programmed treatment strategy was modified in 11 out of 30 patients (37%) after the definition of final stage. If we considered the 123 CT staged patients with localized stage, ten patients (8%) with a change of stage from localized to advanced after PET evaluation were treated with different strategy. FDG-PET was shown to be a relevant, non-invasive method that supplements conventional procedures and should therefore be used routinely to stage HL, particularly in early stage patients, where a change in stage may modify disease management.

Interleukin-15: A Novel Cytokine with Regulatory Properties on Normal and Neoplastic B Lymphocytes

IL-15 is a recently discovered cytokine that shares biological activities with IL-2. Although the biological functions displayed by these two molecules overlap to some extent, they are produced by different cell types and bind to distinct receptorial structures. Both cytokines transduce signals through the beta (p75) and gamma (p64) chains of the IL-2R system, but IL-15, like IL-2, binds to its own specific alpha chain, referred to as IL-15Ralpha. Similarly to IL-2, IL-15 is able to trigger both the proliferation and immunoglobulin production by normal B-lymphocytes. These biological functions may be acquired however only when B-cells have been preactivated in vitro with polyclonal mitogens, or alternatively, when they are cultured in association with other stimuli. By contrast, leukemic cells from patients with chronic B-cell malignancies, including B-cell chronic lymphocytic leukemia and hairy cell leukemia, proliferate to IL-15 regardless of in vitro preactivation. This peculiar IL-15 responsiveness distinguishes malignant B-cells from normal B-lymphocytes. Furthermore, the proliferation elicited by IL-15 in B-CLL and HCL is mainly related to the presence of the beta and gamma chains of the IL-2R system on malignant B-lymphocytes.

Alveolar macrophages as a cell source of cytokine hyperproduction in HIV-related interstitial lung disease.

Pulmonary macrophages play an important role in the pathogenesis of the acquired immunodeficiency syndrome (AIDS). They are known to be discrete target cells for human immunodeficiency virus (HIV), and compelling evidence is accumulating that alveolar macrophages (AMs) from HIV‐infected patients behave as versatile secretory cells that, acting as antigen‐presenting cells, release a great variety of cytokines. The secretory products of AMs, pivotal to their immune effects, may contribute to localized immune dysregulation as well as to primary lung damage and clinical disease. Pulmonary macrophages are also thought to facilitate retroviral spread by their direct infection, by presenting HIV antigens to uninfected T cells, and by secreting cytokines that trans‐activate HIV expression. This review briefly considers the events underlying the role of AMs in the pulmonary defense mechanisms against HIV and AIDS‐related opportunistic infections. Following a brief overview of immune mechanisms taking place in the lungs of HIV‐infected subjects, we describe the specific role of AMs in the immune mechanisms devoted to recognizing and removing HIV‐infected cells and controlling the local growth of opportunists. The pathogenetic role envisaged for macrophages in lung damage are also reviewed in the context of the known biology of these cells. Finally, this review examines the relevance of the retroviral infection of AMs in terms of pathogenesis of the HIV‐related interstitial lung disease.

Current and future management of Ph/BCR-ABL positive ALL.

Following the introduction of targeted therapy with tyrosine kinase inhibitors (TKI) at the beginning of the past decade, the outcome of patients with Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) has dramatically improved. Presently, the use of refined programs with first/second generation TKI’s and chemotherapy together with allogeneic stem cell transplantation allow up to 50% of all patients to be cured. Further progress is expected with the new TKI ponatinib, overcoming resistance caused by T315I point mutation, other targeted therapies, autologous transplantation in molecularly negative patients, therapeutic monoclonal antibodies like inotuzumab ozogamicin and blinatumomab, and chimeric antigen receptor-modified T cells. Ph+ ALL could become curable in the near future even without allogeneic stem cell transplantation, minimizing the risk of therapy-related death and improving greatly the quality of patients’ life.

Skewing of the T-cell receptor repertoire in the lung of patients with HIV-1 infection

ObjectivesA bias of the use of T-cell receptor (TCR) Vβ regions has been reported both in peripheral blood and in several tissues in patients with AIDS, including lymph nodes, spleen and salivary glands. Although the disease is frequently characterized by an infiltration of T cells in the lung interstitium, no information is presently available on the configuration of the TCR repertoire in this microenvironment. This study was performed to address the question of whether a bias in T-cell selection occurs in the lung of patients with AIDS. MethodsTCR β-chain variable region (TCR-Vβ) repertoire was analysed by flow cytometry and polymerase chain reaction (PCR) analyses in blood and lung lymphocytes of 13 patients with HIV-1 infection at different stages of the disease. Blood and lung lymphocytes were also assessed for their responsiveness to different superantigenic stimuli represented by staphylococcal enterotoxins (SEA, SEB, SEC1, SEC2, SED and SEE). ResultsFlow cytometry analysis in AIDS patients demonstrated an overexpression of cells bearing Vβ2 and Vβ3 gene segments in the lung compared with peripheral blood of the same subjects, as well as to lung and blood lymphocytes of normal controls. PCR analysis performed in AIDS patients extended these observations and demonstrated a significant bias also in the use of T cells bearing Vβ7 and Vβ9 gene regions in the lung compartment with respect to the blood. Virtually all T cells bearing the over-represented Vβ segment belong to the CD8 subset. Interestingly, T-lymphocyte response to different superantigens demonstrated a low proliferative rate in the lung with respect to the blood in HIV-1-infected patients. ConclusionsThese findings indicate a compartmentalization of cells bearing discrete Vβ gene products in the pulmonary microenvironment of patients with AIDS and suggest that the expansion of specific-Vβ region subsets occurring in the lung might result from triggering by a superantigen.

Lung Lymphocytes: Origin, Biological Functions, and Laboratory Techniques for Their Study in immune-Mediated Pulmonary Disorders

Different types of immunocompetent cells, including T lymphocytes and alveolar macrophages, account for pulmonary host defense. Taking advantage of the availability of the monoclonal antibody technique, cell culture facilities, pure recombinant cytokines, and molecular probes for their genes, in the last few years it has been possible to keenly study the different steps that lead to the compartmentalization of immune response in human lung. Furthermore, the immunological analysis of cells retrieved from bronchoalveolar lavage (BAL) allowed recognition of the importance of immune mechanisms in the evolution of immune-mediated pulmonary disorders. The purpose of this review is to summarize recent advances on the immunologic characterization of lung lymphocytes in health and disease. Following a brief description of the pathways through which the pulmonary lymphoid system contributes to removing potentially harmful inhaled antigenic materials, available laboratory techniques to evaluate the lymphoid component of the pulmonary immune system and their byproducts are discussed. These techniques cover methods for preparing lymphocytes from the BAL fluid and for characterizing lung lymphocytes both in cell suspensions and pulmonary tissue biopsies. Other sections of this review describe the techniques for measuring the immunologic effector functions of lung lymphocytes. We also provide the reader with a flavor of the molecular biology methods used to characterize lymphocytes in the pulmonary microenvironment. The final sections of the review article highlight the pathogenetic role envisaged for lymphoid cells in pulmonary disease states and emphasize the importance of the BAL analysis in the clinical management of the most relevant immune-mediated lung disease.

Bendamustine in chronic lymphocytic leukemia: Outcome according to different clinical and biological prognostic factors in the everyday clinical practice

Bendamustine proved to be effective for the treatment of chronic lymphocytic leukemia (CLL). However, the relationship between its activity with clinico‐biological prognosticators has been addressed only in few studies. We retrospectively evaluated the efficacy of bendamustine, in a real‐life contest, on 142 patients, median age 70 years, median number of previous regimens 2 (0–8, 13% previously untreated). Bendamustine was administered for a median number of 4 cycles, in 84% of cases with rituximab. Overall (ORR) and complete response (CRR) rates were 68 and 16.5%, respectively. Multivariate analysis demonstrated a relationship between ORR and number of prior treatments (OR 0.25, 95% CI 0.08–0.71; P = 0.009), del(17p) (OR 0.10, 95% CI 0.03–0.32; P < 0.001) and concomitant rituximab (OR 4.37, 95% CI 1.12–17.04; P = 0.033). The estimated 1‐ and 2‐years overall survival (OS) and progression free survival (PFS) rates were 76, 61, 51, and 26%, respectively. Previous sensitivity to fludarabine (HR 0.36, 95% CI 0.16–0.82), response to bendamustine (HR 0.21, 95% CI 0.10–0.45), and del(17p) (HR 2.18, 95% CI 1.002–4.74) had a prognostic significance in multivariate analysis for PFS, while the number of previous therapies (HR 3.48, 95% CI 1.29–9.38; P = 0.014), concomitant use of rituximab (HR 0.32, 95% CI 0.11–0.93) and response to bendamustine (HR 0.22, 95% CI 0.07–0.66) were significant for OS. Side effects included grade 3–4 neutropenia, infections, thrombocytopenia and anemia which occurred in 40, 14, 14, and 10% of patients, respectively. These results confirm the activity and safety of bendamustine and rituximab combination even in patients with unfavorable clinical and biological features excluding del(17p). Am. J. Heamtol. 88:955–960, 2013.

Burkitt lymphoma in adolescents and young adults: management challenges

About one-half of all Burkitt lymphoma (BL) patients are younger than 40 years, and one-third belong to the adolescent and young adult (AYA) subset, defined by an age between 15 and 25–40 years, based on selection criteria used in different reports. BL is an aggressive B-cell neoplasm displaying highly characteristic clinico-diagnostic features, the biologic hallmark of which is a translocation involving immunoglobulin and c-MYC genes. It presents as sporadic, endemic, or epidemic disease. Endemicity is pathogenetically linked to an imbalance of the immune system which occurs in African children infected by malaria parasites and Epstein–Barr virus, while the epidemic form strictly follows the pattern of infection by HIV. BL shows propensity to extranodal involvement of abdominal organs, bone marrow, and central nervous system, and can cause severe metabolic and renal impairment. Nevertheless, BL is highly responsive to specifically designed short-intensive, rotational multiagent chemotherapy programs, empowered by the anti-CD20 monoclonal antibody rituximab. When carefully applied with appropriate supportive measures, these modern programs achieve a cure rate of approximately 90% in the average AYA patient, irrespective of clinical stage, which is the best result achievable in any aggressive lymphoid malignancy to date. The challenges ahead concern the following: optimization of management in underdeveloped countries, with reduction of diagnostic and referral-for-care intervals, and the applicability of currently curative regimens; the development of lower intensity but equally effective treatments for frail or immunocompromised patients at risk of death by complications; the identification of very high-risk patients through positron-emission tomography and minimal residual disease assays; and the assessment in these and the few refractory/relapsed ones of new monoclonals (ofatumumab, blinatumomab, inotuzumab ozogamicin) and new molecules targeting c-MYC and key proliferative steps of B-cell malignancies.

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.

Human Immunodeficiency Virus and the Lung

The primary function of the immune system is to maintain the integrity of the host by eliminating microbial infringements without clinical sequelae. The lung has the capacity to initiate and regulate immune responses against microbial invasion and neoplastic transformation. Mechanical mechanisms and innate host defences are important to avoid infections of the lung, but the respiratory tract is also equipped with an extraordinary repertoire of immunologically competent cells capable of eliciting protective effector functions [1–3]. Among these, the major initiators and regulators of the pulmonary immune system are alveolar macrophages (AMs), dendritic cells (DCs) and pulmonary T cells which, interacting with each other either directly or via cytokines, activate a variety of alloreactive responses to clear foreign antigens [1–3].